Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

in Endocrine-Related Cancer
Authors:
C R C Pieterman Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands

Search for other papers by C R C Pieterman in
Current site
Google Scholar
PubMed
Close
,
E B Conemans Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands
Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands

Search for other papers by E B Conemans in
Current site
Google Scholar
PubMed
Close
,
K M A Dreijerink Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands

Search for other papers by K M A Dreijerink in
Current site
Google Scholar
PubMed
Close
,
J M de Laat Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands

Search for other papers by J M de Laat in
Current site
Google Scholar
PubMed
Close
,
H Th M Timmers Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands

Search for other papers by H Th M Timmers in
Current site
Google Scholar
PubMed
Close
,
M R Vriens Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands

Search for other papers by M R Vriens in
Current site
Google Scholar
PubMed
Close
, and
G D Valk Division of Internal Medicine and Dermatology, Division of Biomedical Genetics, Division of Surgical Specialties, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands

Search for other papers by G D Valk in
Current site
Google Scholar
PubMed
Close

Free access

Sign up for journal news

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2–8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

Abstract

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2–8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

Introduction

Thoracic and duodenopancreatic neuroendocrine tumors (dpNETs) can occur either sporadically or as a manifestation of an inherited syndrome, most importantly the multiple endocrine neoplasia type 1 (MEN1) syndrome. This is an autosomal dominantly inherited disease that is caused by germline mutations in the MEN1 gene. NETs associated with MEN1 are lung NETs, thymic NETs (thNETs), gastrin NETs, and dpNETs. MEN1-related NETs are an important cause of morbidity and presently malignant dpNETs and thNETs are the main cause of MEN1-related death (Schaaf et al. 2007, Goudet et al. 2010).

In the past decade, understanding of the genetic and molecular aspects of NETs has increased and important steps have been made in the therapy of advanced disease. New tumor classification and staging systems have improved patient care and uniformity in patient selection for clinical trials. It is important to recognize similarities in the tumorigenesis of MEN1-related and sporadic NETs, because MEN1-related NETs may be regarded as a model for sporadic disease. On the other hand, it is also essential to be aware of potential differences in tumor behavior between these two entities, as this influences diagnostic and therapeutic strategies.

In this review, we provide a comprehensive overview of the literature concerning tumor development of MEN1-related dpNETs and thoracic NETs (Box 1). The complete spectrum, from epidemiologic characteristics and natural history to important molecular findings associated with loss of the MEN1 gene, is discussed. Differences between and similarities with their sporadic counterparts are highlighted. Table 1 provides a list of some of the abbreviations used in the text.

Box 1: Search strategy

The contents of this review are based on the experience of the authors and on an extensive search in PubMed. The following terms were used in the search string: ‘MEN1’ and all relevant synonyms OR ‘menin’ and all relevant synonyms. For lung NET, this search string was combined with ‘bronchial’ OR ‘pulmonary’ OR ‘lung’ (and relevant synonyms) AND ‘carcinoid’ OR ‘neuroendocrine’. For thNET this search string was combined with ‘thymic’ OR ‘thymus’ OR ‘mediastinal’ AND ‘carcinoid’ OR ‘neuroendocrine’. For dpNET, this search string was combined with all relevant synonyms for ‘pancreas’ and ‘duodenum’ AND all relevant synonyms for ‘neuroendocrine tumor’ OR ‘gastrinoma’ OR ‘insulinoma’ OR ‘glucagonoma’ OR ‘VIPoma’.

Table 1

Abbreviations used in the text

ACAtypical carcinoid
DIPNECHDiffuse idiopathic pulmonary neuroendocrine cell hyperplasia
dpNETDuodenopancreatic neuroendocrine tumor
H3K4me3Trimethylation of lysine 4 on histone 3
HDACHistone deacetylase
LOHLoss of heterozygosity
MEN1Multiple endocrine neoplasia type 1
NETNeuroendocrine tumor
NFNonfunctioning
NF-pNETNonfunctioning pancreatic neuroendocrine tumor
NRNuclear receptor
pNETPancreatic neuroendocrine tumor
thNETThymic neuroendocrine tumor
TCTypical carcinoid
TFTranscription factor
VIPomaVaso-active intestinal peptide producing neuroendocrine tumors

MEN1 gene

The MEN1 gene was initially localized to chromosome 11q13 by linkage analysis and tumor deletion mapping studies (Larsson et al. 1988, Friedman et al. 1989, Byström et al. 1990, Lubensky et al. 1996), which led to the identification of the gene in 1997 (Chandrasekharappa et al. 1997, Lemmens et al. 1997). More than 450 different germline MEN1 mutations have been identified in MEN1 patients (Lemos & Thakker 2008). MEN1 consists of ten exons and mutations are found scattered throughout the gene. The protein product is the 610-amino acid protein, called menin. Most MEN1 gene mutations are predicted to lead to truncation of the protein (Lemos & Thakker 2008). Missense mutations have been reported in about 20% of the cases. Both truncated and missense mutations result in reduced levels of protein due to proteolytic degradation via the ubiquitin–proteasome pathway (Yaguchi et al. 2004). A small percentage of patients who are considered to have the MEN1 syndrome (based on the clinical definition) may not harbor a germline mutation within the coding region of the MEN1 gene (Agarwal et al. 1997). Possibly, these patients have mutations in the promoter region or large deletions on chromosome 11q13 (Cavaco et al. 2002). Currently, in clinical practice, inconclusive DNA sequencing is followed by multiplex ligation-dependent probe amplification analysis for detection of large deletions. An alternative explanation for the MEN1 syndrome of these patients may include epigenetic silencing of MEN1 (e.g. by DNA methylation) or mutations in other genes, which cause MEN1-like manifestations.

The MEN1 gene is a tumor suppressor gene for endocrine tissues. According to Knudson's ‘two-hit hypothesis’, biallelic inactivation of MEN1 is required for tumor development (Knudson 1971). This second hit typically involves large chromosomal deletions in chromosome 11q13. Loss of heterozygosity (LOH) of MEN1 is demonstrated in most reported MEN1-related pancreatic NETs (pNETs) (Lubensky et al. 1996, Debelenko et al. 1997b, Hessman et al. 2001, Perren et al. 2007). However, the frequency of LOH of chromosome 11q13 in MEN1-related primary duodenal gastrinomas is only 21–45% (Lubensky et al. 1996, Debelenko et al. 1997b). LOH of chromosome 11q13 has also been shown in MEN1-related pulmonary carcinoids (Debelenko et al. 1997b, Dong et al. 1997). Intriguingly, no LOH was found in thNETs (Teh et al. 1994, 1998, Hessman et al. 2001, Gibril et al. 2003). In these cases, other events might be involved in silencing the second MEN1 allele. Somatic mutations in MEN1-related tumors have been reported as an alternative mechanism leading to the inactivation of this second MEN1 allele (Pannett & Thakker 2001). Post-transcriptional reduction in menin levels by specific microRNAs may mimic the second hit (Luzi et al. 2012). In sporadic NETs, somatic mutations of the MEN1 gene have been found. The reported frequency for MEN1 mutations in sporadic pNETs is up to 44% in well-differentiated tumors (Jiao et al. 2011). In accordance with Knudson's hypothesis, LOH of chromosome 11q13 is also observed in sporadic pNETs (Debelenko et al. 1997b, Hessman et al. 1998, Gortz et al. 1999). Also, in sporadic pulmonary carcinoids, mutations in the MEN1 gene and LOH of chromosome 11q13 are reported with a frequency of 18–45% (Debelenko et al. 1997b, Walch et al. 1998, Gortz et al. 1999, Petzmann et al. 2001, Vageli et al. 2006, Veschi et al. 2012) and up to 73% in a single report (Finkelstein et al. 1999). Apparently, MEN1-related tumors and their sporadic counterparts share common pathways in tumor development.

Thoracic NETs in MEN1

Pathology and pathogenesis

According to the World Health Organization, lung and thymus NETs are classified into typical carcinoids (TCs), atypical carcinoids (ACs), and high-grade neuroendocrine carcinomas based on mitotic count and the presence of necrosis (Travis et al. 2004). High-grade tumors are divided into large-cell neuroendocrine carcinomas and small-cell carcinomas. Small (<0.5 cm) pulmonary tumors with carcinoid morphology are called tumorlets (Travis et al. 2004). For thNETs, alternative grading systems exist, which is important to realize when comparing and interpreting results from different studies (Fukai et al. 1999, Moran & Suster 2000a, Gal et al. 2001, Gaur et al. 2010).

Pulmonary carcinoids have a different clinical presentation and genetic profile compared with high-grade tumors and must be regarded as a separate entity (Swarts et al. 2012). High-grade lung NETs are not seen in association with MEN1. Moreover, in contrast to sporadic pulmonary carcinoids, mutations in the MEN1 gene and LOH at chromosome 11q13 are rare in high-grade lung NETs (Swarts et al. 2012). This sharp distinction is absent in thNETs (Moran & Suster 2000b) and MEN1-related thNETs include both well- and poorly-differentiated neuroendocrine carcinomas.

The cell of origin for pulmonary carcinoids is thought to be the pulmonary neuroendocrine cell (Swarts et al. 2012), although, some suggest an uncommitted progenitor cell (Warren & Hammar 2006). Pulmonary neuroendocrine cells are evenly distributed throughout the airways, but absent from the alveoli, and comprise 0.4% of all lung epithelial cells (Boers et al. 1996). In response to various triggers, reactive neuroendocrine cell hyperplasia can occur, which is not associated with the development of pulmonary carcinoids. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), on the other hand, is a rare disorder that is considered preneoplastic to pulmonary carcinoids (Aguayo et al. 1992, Travis et al. 2004). Only one case of a MEN1-patient with DIPNECH has been published to date (Davies et al. 2007). However, in published cases of MEN1-related pulmonary carcinoids, pathology of surrounding lung tissue was not reported, so the true prevalence of DIPNECH among MEN1-patients is unknown.

The cell of origin for thNETs is not known and there are no known precursor lesions. thNETs were first described in 1972 and in the same year the association with MEN1 was reported (Rosai & Higa 1972, Rosai et al. 1972). It was then hypothesized that these tumors arise from neuroendocrine cells residing within the normal thymus. In different series, family clustering of MEN1-related thNETs was demonstrated (Teh et al. 1997, 1998, Ferolla et al. 2005, Goudet et al. 2009). In those series, no apparent MEN1 genotype–phenotype correlation was seen, suggesting the involvement of other genetic factors.

Epidemiology

The prevalence of thNETs among MEN1 patients is 2–8% (Teh et al. 1997, Burgess et al. 1998b, Gibril et al. 2003, Goudet et al. 2011, Sakurai et al. 2013). Approximately one-fifth of all thNETs are MEN1-related (Teh et al. 1997), therefore the diagnosis of a thNET should always prompt further evaluation of a possible underlying MEN1 syndrome (de Laat et al. 2012). Mean age at diagnosis of thNETs in MEN1 is 39–47 years (Teh et al. 1997, 1998, Gibril et al. 2003, Ferolla et al. 2005, Goudet et al. 2009, Sakurai et al. 2013). In series from USA, Europe, and Australia 95–100% of the patients are male (Teh et al. 1997, 1998, Gibril et al. 2003, Ferolla et al. 2005, Goudet et al. 2009), whereas in a recent Japanese series 64% of thNETs occurred in males (Sakurai et al. 2013). Age at diagnosis is 43–58 years in sporadic thNET and male predominance, although less pronounced (67–86%), is also seen (de Montpreville et al. 1996, Soga et al. 1999, Moran & Suster 2000a, Gaur et al. 2010, Hamaji et al. 2012). It is important to note that most MEN1-patients with thNETs are heavy smokers (Teh et al. 1997, 1998, Gibril et al. 2003, Ferolla et al. 2005).

The exact prevalence of pulmonary carcinoids in MEN1 is unknown. Commonly reported figures are 3–8% (Marx et al. 1998, Karges et al. 2000, Goudet et al. 2011). However, in a large Tasmanian family (n=129), prevalence among patients screened with thoracic computed tomography ranged from 11% if only pathology proven cases were included to 31% based on radiological findings (Sachithanandan et al. 2005). Reported age at diagnosis of MEN1-related pulmonary carcinoids is mid-forties (Sachithanandan et al. 2005). Although initially a female predominance was reported (Duh et al. 1987, Farhangi et al. 1987, Shepherd 1991, Sachithanandan et al. 2005), the prevalence appears to be equal between genders in a large recent study (Goudet et al. 2011).

Natural history and prognostic factors: pulmonary carcinoids

Very little is known about the natural course and prognosis of pulmonary carcinoids in MEN1. Evidence is limited to one small series and several case reports or descriptions, either separately published or mentioned within larger MEN1 patient series. Among sporadic pulmonary carcinoids, TCs are much more frequent than ACs (10–27% in series also including nonsurgical patients; Fink et al. 2001, Pusceddu et al. 2010, Naalsund et al. 2011, Okoye et al. 2013). This seems to be similar in MEN1, but classifications are rarely reported (Murat et al. 1997, Snabboon et al. 2005, Lourenco-Jr et al. 2007, Abe et al. 2008, Divisi et al. 2008, Matsuda et al. 2010, Montero et al. 2010). As in other MEN1 manifestations, multiplicity seems to be common in pulmonary carcinoids (Marx et al. 1998, Sachithanandan et al. 2005). In its sporadic counterpart, multiplicity is seen in <1–9% (Daddi et al. 2004, Garcia-Yuste et al. 2007, Ferolla et al. 2009, Okoye et al. 2013). Ectopic hormone production is not reported in MEN1-related pulmonary carcinoids, in contrast to sporadic disease (Boddaert et al. 2012, Garby et al. 2012, Simonds et al. 2012).

The overall survival of MEN1-related pulmonary carcinoids is unknown. In series focusing on MEN1-related mortality, 5–9% of the MEN1-related deaths occurring before 1990 were attributed to pulmonary carcinoids (Wilkinson et al. 1993, Goudet et al. 2010), with no deaths due to pulmonary carcinoids reported after 1990 (Geerdink et al. 2003, Wilson et al. 2008, Goudet et al. 2010). In line with these findings, pulmonary carcinoids do not give an increased risk of death in MEN1 patients (Goudet et al. 2010).

The prevalence of lymph node or distant metastases is difficult to establish in MEN1-related pulmonary carcinoids. In a total of only 33 cases reported in literature, information on metastases is available, with 24% lymph node metastases and 12% distant metastases (Underdahl et al. 1953, Williams & Celestin 1962, Dry et al. 1975, Farhangi et al. 1987, Shepherd 1991, Murat et al. 1997, Sachithanandan et al. 2005, Snabboon et al. 2005, Lourenco-Jr et al. 2007, Abe et al. 2008, Divisi et al. 2008, Waldmann et al. 2009, Fabbri et al. 2010, Matsuda et al. 2010, Montero et al. 2010).

Given the paucity of data on pulmonary carcinoids in MEN1 and the absence of head-to-head comparisons, it is unclear whether the natural history differs between MEN1-related and sporadic pulmonary carcinoids. There are a few studies in sporadic tumors that show somatic MEN1 mutations, LOH at 11q13, or reduced MEN1 gene expression to be an adverse prognostic factor (Debelenko et al. 1997a, Petzmann et al. 2001, Swarts et al. 2011).

Factors predicting development of metastases or survival are not known in MEN1-related pulmonary carcinoids. In their sporadic counterparts ACs, lymph node metastases, distant metastases, and higher proliferation rate (Ki67 labeling index or mitotic index) have been repeatedly identified as adverse prognostic factors (Cao et al. 2011, Daddi et al. 2013). Results on the prognostic values of gender, age, and tumor size are contradictory.

Natural history and prognostic factors: thNET

Six case series including more than five patients have been published on thNETs in MEN1 (Teh et al. 1997, 1998, Gibril et al. 2003, Ferolla et al. 2005, Goudet et al. 2009, Sakurai et al. 2013). In these series, classifications are often not reported (Teh et al. 1997, 1998, Gibril et al. 2003, Sakurai et al. 2013). When mentioned, 100% are AC in one series and 38% poorly differentiated neuroendocrine carcinomas in another (with the distinction between TC and AC for the other 62% not reported; Ferolla et al. 2005, Goudet et al. 2009). In sporadic thNETs the reported frequencies vary greatly, TCs are reported in 0–67% in different series and 81% in a literature review from 1999 (de Montpreville et al. 1996, Fukai et al. 1999, Soga et al. 1999, Moran & Suster 2000a, Gaur et al. 2010, Cardillo et al. 2012). Patient selection and differences in the use of grading systems may explain this variation. Cushing's syndrome due to ectopic adrenocorticotropic hormone production is rare in MEN1-related thNETs (0–5%; Teh et al. 1997, 1998, Gibril et al. 2003, Ferolla et al. 2005, Goudet et al. 2009, Sakurai et al. 2013), but it has been observed in 5–31% of the sporadic cases (Moran & Suster 2000a, Kondo & Monden 2003, Cardillo et al. 2012).

Among the manifestations of the MEN1 syndrome, thNETs carry the highest risk of death (Goudet et al. 2010) with an estimated 10-year survival of 30–36% (Goudet et al. 2009, Sakurai et al. 2013). Although mortality is high, the course of MEN1-related thNETs may be protruded, with one series reporting a median survival of 9.6 years (Goudet et al. 2009). When comparing six MEN1 patients with thNETs with 22 patients with sporadic thNETs, Crona et al. (2013) found no survival difference between these groups.

In MEN1-related thNETs, 90% disease-related mortality was reported among patients with advanced stage disease in a series with a mean 3.6 years follow-up (Teh et al. 1997). In the other series, patients were followed for a mean 5–7 years and metastases occurred in 32–71% of the patients. Disease-related mortality in these series ranged from 0 to 43% (Teh et al. 1998, Gibril et al. 2003, Ferolla et al. 2005, Goudet et al. 2009, Sakurai et al. 2013). In one of the two series reporting no mortality, the majority was discovered incidentally at prophylactic thymectomy or by screening (Gibril et al. 2003).

No data are available on prognostic factors with regard to overall survival, recurrence, or metastases in MEN1 patients. In series reporting on sporadic thNETs, prognostic factors related to decreased survival are higher tumor grade, more advanced disease, higher Ki67 labeling index (cut-off 10%), and larger tumor size (Moran & Suster 2000a, Gal et al. 2001, Gaur et al. 2010, Cardillo et al. 2012, Crona et al. 2013).

dpNETs in MEN1

Pathology and pathogenesis

dpNETs are classified according to the European Neuroendocrine Tumor Society/World Health Organization grading system into three grades based on proliferation rate (Rindi et al. 2006, Bosman et al. 2010).

The hallmark of dpNETs in MEN1 is multiplicity, which is in contrast to the mostly solitary sporadic dpNETs (Thompson et al. 1984, Pipeleers-Marichal et al. 1993, Crippa et al. 2012). All histologic subtypes can occur in MEN1. At pathology, all MEN1 patients have multiple micro-adenomas (pNETs <5 mm without clinical syndrome) dispersed throughout the pancreas associated with one or more NETs ≥5 mm (Thompson et al. 1984, Kloppel et al. 1986, Le Bodic et al. 1996, Anlauf et al. 2006b). These multiple dpNETs in MEN1 arise from independent clonal events, as demonstrated by different allelic deletion and retention patterns in synchronous tumors (Debelenko et al. 1997b, Hessman et al. 1999, Perren et al. 2007). Apart from these tumors other lesions such as islet cell hyperplasia/enlargement, nesidioblastosis, and atypical or monohormonal endocrine cell clusters are frequently observed in the MEN1 pancreas, leading to different theories as to the cell of origin for pNETs (Thompson et al. 1984, Le Bodic et al. 1996, Vortmeyer et al. 2004, Perren et al. 2007). Normal pancreatic islets and alternatively ductal/acinar cells are proposed to be the precursor cells for pNETs (Vortmeyer et al. 2004, Perren et al. 2007).

Gastrinomas take a special place among the MEN1-related dpNETs, as the vast majority are not pancreatic but located submucosal in the duodenum (Pipeleers-Marichal et al. 1990). Sporadic gastrinomas are located in the duodenum less frequently than in MEN1 (Pipeleers-Marichal et al. 1990, Donow et al. 1991, Pipeleers-Marichal et al. 1993, Anlauf et al. 2006a). Duodenal NETs in MEN1 are almost always multiple, while sporadic duodenal NETs are usually solitary (Pipeleers-Marichal et al. 1990, Donow et al. 1991, Anlauf et al. 2006a). In MEN1, they are associated with multifocal hyperplasia of gastrin and somatostatin producing cells, which are proposed to be precursor lesions (Anlauf et al. 2005).

Epidemiology

The clinical prevalence of dpNETs in MEN1 is over 50% in recent large series (Goudet et al. 2011, Sakurai et al. 2012a) and the penetrance of clinically manifest dpNETs at the age of 80 is 84% (Triponez et al. 2006a).

dpNETs are classified as hormonally active or nonfunctioning (NF) based on the combination of clinical features, laboratory results, and findings at immunohistochemistry. In the MEN1 syndrome, synchronous dpNETs may secrete different hormones based on immunohistochemistry (Le Bodic et al. 1996, Anlauf et al. 2006b). As these findings do not always correlate with clinical symptoms, classifications should not be based on immunohistochemistry alone.

When sought for, additional NF-pNETs are found in all patients undergoing surgery for functional tumors, so the prevalence of NF-pNETs is probably equal to dpNETs in general (Tonelli et al. 2006, Lopez et al. 2011, Giudici et al. 2012). Gastrinoma is the most prevalent hormonally active dpNET (29–55% of all dpNETs in studies published in the last decade), followed by insulinoma (2–24%) and rare functioning tumors seen in <10% such as glucagonoma, vaso-active intestinal peptide-producing NET (VIPoma), and somatostatinoma. (Lourenco-Jr et al. 2007, Vierimaa et al. 2007, Pieterman et al. 2009, Waldmann et al. 2009, Goudet et al. 2011, Sakurai et al. 2012a). It is important to realize that 76% of all cases of growth hormone (GH)-releasing hormone-producing pNETs reported in literature are MEN1-related (Garby et al. 2012). This diagnosis should therefore always raise suspicion of an underlying MEN1 syndrome. Separating different types of dpNETs in MEN1 is somewhat artificial, because most patients with hormonally active tumors will harbor additional NF-pNETs (Tonelli et al. 2006, Lopez et al. 2011, Giudici et al. 2012), patients with NF-pNETs can develop hormonally active tumors (Thomas-Marques et al. 2006, Davi et al. 2011), and co-occurrence of different hormonally active tumors has also been described (Tonelli et al. 2006, Giudici et al. 2012).

MEN1-related dpNETs are seen one to two decades earlier than their sporadic counterparts (Jensen 1998, Nikfarjam et al. 2008, Anlauf et al. 2009, Crippa et al. 2012, Singh et al. 2012). Insulinomas have the lowest age of onset (patients are usually in their twenties to thirties at diagnosis), patients with gastrinomas and NF-pNETs are usually diagnosed in their thirties (Jensen 1998, Cougard et al. 2000, Triponez et al. 2006a, Sakurai et al. 2012b). At the age of 60, the penetrance of gastrinoma is significantly higher in men (55%) compared with women (33%), while the other dpNET types do not show gender differences (Goudet et al. 2011).

Natural history

dpNETs are the most important determinant of MEN1-related survival. In historical series, ulcer disease due to gastrinoma was the most important cause of MEN1-related death (Ballard et al. 1964), while this presently is malignant dpNETs (Schaaf et al. 2007, Goudet et al. 2010). In patients with MEN1-related dpNETs, estimated 10-year survival is 75% (Carty et al. 1998, Kouvaraki et al. 2006). Risk of death seems to differ between the various subtypes, with the rare functioning tumors presenting the highest risk followed by NF-pNETs and gastrinoma, while insulinomas do not seem to increase the risk of death (Goudet et al. 2010).

However, the natural history of NF-pNETs is not well-established yet. Estimated 10-year survival rates of 23–62% have been reported (Levy-Bohbot et al. 2004, Kouvaraki et al. 2006), whereas this was 100% in a recent series (Lopez et al. 2011). One has to keep in mind that with endoscopic ultrasound, more small NF-pNETs are currently diagnosed. They are usually indolent and demonstrate slow growth, with a doubling time of 5–10 years (Kann et al. 2006, Sakurai et al. 2007). When 46 patients with NF-pNETs <2 cm without surgical treatment were followed over 10 years, 17% showed increase in size, 11% developed a functional syndrome, 65% displayed stable disease, 2% died due to metastatic NF-pNETs, 2% due to other causes, and 2% was lost to follow-up (Triponez F, Goudet P, AFCE, & GTE unpublished observations presented at ENETS 2013, Barcelona, Spain). In the largest reported series on NF-pNETs (n=108), metastases, mostly distant, are seen in 19% and disease-specific survival is 91% after a mean follow-up of 4 years (Triponez et al. 2006a). In smaller series from the last decade, distant metastases are reported in 6–22% (Bartsch et al. 2005, Davi et al. 2011, Lopez et al. 2011), whereas in a report from 1992 distant metastases were observed in 57% (Grama et al. 1992). Mean tumor size in this latter series was 6.7 cm (Grama et al. 1992).

In MEN1-related insulinomas, reported survival rates in series with more than ten patients are 93–100% after 9–10 years of follow-up (Van Box Som et al. 1995, Cougard et al. 2000, Proye et al. 2004). Multiple insulinomas are seen in 25–83% (Van Box Som et al. 1995, Thompson 1998, Giudici et al. 2012), whereas in sporadic insulinomas multiplicity is seen in ∼4% (Nikfarjam et al. 2008, Anlauf et al. 2009, Crippa et al. 2012).

Malignancy in MEN1-related insulinomas has been reported in 5–27% in series including more than ten patients (Cougard et al. 2000, Proye et al. 2004, Crippa et al. 2012). In these malignant insulinomas, liver metastases were only seen once (Proye et al. 2004).

The natural history of gastrinomas in MEN1 is difficult to establish for several reasons. First, gastrinomas in MEN1 are predominantly located in the duodenum (Pipeleers-Marichal et al. 1990). In series on MEN1-related gastrinomas, high rates of pancreatic tumors might be reported, but most of these will not be the gastrinomas. Rates of pancreatic gastrinomas are only 0–18% in series that include immunohistochemistry in the classification of pNETs as gastrinomas (Tonelli et al. 2006, Dickson et al. 2011, Imamura et al. 2011, Lopez et al. 2013). Second, MEN1-related gastrinomas are almost invariably accompanied by NF-pNETs (Thompson 1998, Dickson et al. 2011). If distant metastases arise, these can not only be caused by the gastrinoma, but also by the accompanying NF-pNETs and even by NETs of other locations, which cannot be separated if no pathology or immunohistochemistry results are available. Third, when interpreting the results of clinical series, it is important to realize that in surgical series synchronous metastases will most likely be underrepresented, since diffuse liver metastases are seen as a contra-indication for surgery, whereas in series with low surgical rates nodal status will most likely be underrepresented, because this is difficult to establish on imaging (Skogseid et al. 1998). Finally, since the publication of guidelines for periodic evaluation, MEN1 patients must be viewed as a screened population, making comparison with sporadic cases more difficult (Thakker et al. 2012).

The reported 10-year survival of gastrinomas in MEN1 is 86–94% (Thompson 1998, Norton et al. 2001, Ito et al. 2013), with two series reporting 63 and 75% (Melvin et al. 1993, Ruszniewski et al. 1993). In MEN1-related gastrinoma, synchronous lymph node metastases are reported in 45–69% (Ruszniewski et al. 1993, Thompson 1995, Weber et al. 1995, Jensen 1998, Norton et al. 1999, 2001, Imamura et al. 2011, Singh et al. 2012, Ito et al. 2013), with two series reporting 23–35% (Thompson 1998, Cadiot et al. 1999) and two series reporting 80%. (Dickson et al. 2011, Lopez et al. 2013). Synchronous distant metastases are reported in 4–29% in series also including nonsurgical patients (Jensen 1998, Ito et al. 2013).

Owing to its rarity, very few data are available on functioning pNETs other than gastrinomas and insulinomas. The largest combined experience comes from the French Endocrine Tumor Study Group, reporting on five glucagonomas, three VIPomas, and two somatostatinomas in MEN1, comprising 3.3% of the MEN1-related dpNETs (Levy-Bohbot et al. 2004). Four of these ten patients had liver metastases (40%). Ten-year survival was 54% (Levy-Bohbot et al. 2004).

Natural history: comparison with sporadic dpNET

Some series including MEN1 and sporadic dpNETs of all subtypes report MEN1 to be associated with better survival. However, no separate baseline characteristics are provided for MEN1 patients, so selection bias cannot be excluded (Tomassetti et al. 2005, Fendrich et al. 2007, Rindi et al. 2012). In one study including only patients operated upon for advanced dpNETs (all subtypes), patients with MEN1 had a trend toward better survival and developed no new distant metastases, while 46% of the patients with sporadic dpNETs did develop new distant metastases (Fendrich et al. 2006). The meaning of these findings is difficult to discern, given the highly selected source population.

With regard to different subtypes of dpNETs, no studies are available comparing MEN1-related and sporadic NF-pNETs. In series comparing MEN1-related with sporadic insulinomas, a higher rate of malignancy was seen in MEN1 (Service et al. 1991, Anlauf et al. 2009, Goretzki et al. 2010, Crippa et al. 2012). On gastrinomas more data are available, mostly from different reports of the prospective study on Zollinger–Ellison syndrome by the National Institutes of Health (Weber et al. 1995, Jensen 1998, Norton et al. 1999, Yu et al. 1999). In two of these reports, MEN1 patients had a better overall survival than patients with sporadic gastrinomas but also less advanced disease at baseline, indicating potential lead-time bias (Weber et al. 1995, Jensen 1998). When comparing patients in the same stage of disease, no survival difference was observed between MEN1-related and sporadic gastrinomas (Weber et al. 1995, Norton et al. 1999). Several other studies also point to a similar natural course for MEN1-related and sporadic gastrinomas (Stabile & Passaro 1985, Ruszniewski et al. 1993, Yu et al. 1999, Ellison et al. 2006). In contrast, in one series a survival benefit was found for MEN1 patients, but separate baseline characteristics were not provided (Melvin et al. 1993). Another series also found survival benefit in MEN1, with no significant baseline differences in liver metastases (MEN1 6% vs sporadic 24%, P=0.24), but this might be due to the small number of patients and selection or referral bias cannot be excluded (Singh et al. 2012). Overall, the available data seem to point to a similar natural course for MEN1-related and sporadic gastrinoma.

Prognostic factors

The most important adverse prognostic factor related to overall survival in MEN1-related dpNETs is the presence of liver or other distant metastases (Stabile & Passaro 1985, Cadiot et al. 1999, Kouvaraki et al. 2006, Triponez et al. 2006a, Ito et al. 2013). In a series including all subtypes of dpNETs, the estimated 10-year survival for patients with distant metastases was 34% (Kouvaraki et al. 2006). In patients with diffuse liver metastases from gastrinoma, 10- and 15-year survival of 88 and 52% are reported, while in patients with metastases from NF-pNET 8-year survival was 34% (Norton et al. 2001, Triponez et al. 2006a). Lymph node metastases are not related to survival (Gibril et al. 2001, Kouvaraki et al. 2006, Ito et al. 2013). Contradictory evidence exists with regard to the prognostic value of age. An older age (Burgess et al. 1998a, Cadiot et al. 1999, Kouvaraki et al. 2006, Vierimaa et al. 2007) as well as a younger age are reported as adverse prognostic factors (Gibril et al. 2001, Ito et al. 2013). Reports regarding the prognostic significance of pancreatic tumor size vary. No relation between tumor size and metastases, malignancy or overall survival is found in several series reporting on MEN1-related dpNETs (hormonally active and NF; Grama et al. 1992, Lowney et al. 1998, Lairmore et al. 2000, Bartsch et al. 2005, Kouvaraki et al. 2006, Lopez et al. 2011). In the subset of NF-pNETs, larger tumor size was related to a higher rate of metastases and a decreased overall survival (Triponez et al. 2006a,b). In gastrinoma series, pancreatic tumor size >3 cm was found to be associated with an adverse outcome (Cadiot et al. 1999, Gibril et al. 2001, Ito et al. 2013). However, it is unclear if these pNETs used as prognostic indicator were all gastrinomas and not (in part) coexisting NF-pNETs. Moreover, results from liver biopsy immunohistochemistry are often not reported, so the origin of the metastases cannot be verified. In the natural course of gastrinoma, an aggressive and nonaggressive variant based on tumor growth can be distinguished, with high prognostic relevance (Weber et al. 1995, Sutliff et al. 1997, Yu et al. 1999, Gibril et al. 2001). In MEN1-related gastrinomas, aggressive disease is reported in 15% and in sporadic gastrinomas in ∼25% (Yu et al. 1999, Gibril et al. 2001, Ito et al. 2013). In MEN1 patients, 5-year survival was 100% for patients with nonaggressive disease and 88% for patients with aggressive disease (Gibril et al. 2001). Factors found to be associated with aggressive disease were pancreatic tumor size, liver and bone metastases, markedly increased fasting gastrin level, and the presence of a gastric NET (Gibril et al. 2001).

Mitotic count or Ki67 labeling index has proved to be a very important prognostic factor in sporadic dpNETs (Ekeblad et al. 2008, Scarpa et al. 2010, Rindi et al. 2012), but no information is available for MEN1-related dpNETs.

With regard to the possible prognostic value of genotype, results are contradictory. Nonsense and frameshift mutations in exon 2, 9, and 10 were found to be associated with a more malignant dpNET phenotype (Bartsch et al. 2000, 2005) and inactivating and frameshift mutations showed a trend toward more frequent occurrence in deceased patients (Ito et al. 2013). Others did not find any relation between genotype and the course of dpNETs (Lairmore et al. 2000, Kouvaraki et al. 2002).

Molecular background of MEN1

Menin

The MEN1 gene product, menin, is highly conserved from nematodes and fruit flies to humans. Interestingly, the gene is absent in organisms like yeast and Caenorhabditis elegans. It is predominantly a nuclear protein, which is ubiquitously expressed in both endocrine and non-endocrine organs (Guru et al. 1998, Stewart et al. 1998, Ikeo et al. 2000). It has been challenging to elucidate its biological function, as menin lacks enzymatic activity and initially no homologous domains to other proteins were found. Abolition of menin during mouse embryogenesis is lethal at mid gestation and results in defects in neural tube, liver, and heart (Bertolino et al. 2003a). Its function is tissue-specific, sometimes showing opposite effects between different organs. Many interacting proteins involved in gene transcription and various signaling pathways have been identified (Matkar et al. 2013). Recently, the crystal structure of menin has been elucidated (Murai et al. 2011, Huang et al. 2012). Menin contains a deep pocket that can bind mixed-lineage leukemia 1 (MLL1 or KMT2A) protein or the transcription factor (TF) JUND, with opposite effects on gene transcription (Huang et al. 2012). Further evidence supports a role for menin in DNA repair, through association with replication protein A2 (RPA2; Sukhodolets et al. 2003) and Fanconi anemia complementation group D2 protein (FANCD2; Jin et al. 2003). Subsequent functional experiments characterized menin both as an activator and a repressor of gene transcription. Growing evidence indicates that menin is involved in epigenetic regulation of gene transcription as menin has been shown to be part of chromatin-modifying protein complexes (Box 2). However, it is important to note that most studies focusing on menin interaction partners and its function were conducted in nonendocrine cell lines (Table 2).

Box 2: Gene transcription regulation

In the nucleus of eukaryotic cells, DNA is wrapped around octamers of histone proteins to form nucleosomes. Chromatin is formed by repeating nucleosomes to form beads on a string structures that are converted to the higher order chromatin structures. Chromatin architecture is dynamic and changes in chromatin status influence gene transcription activity (Fig. 1).

 Gene transcription in eukaryotic cells depends on the formation of the so-called pre-initiation complex, which consists of RNA polymerase II and general TFs in relation to the chromatin context. The formation and recruitment of the pre-initiation complex to DNA of gene promoters is modulated by cofactors. These processes are initiated when DNA sequence-specific TFs (e.g. JUND) bind to their corresponding response element on the DNA upstream of the promoter region. Several mechanisms are required for tight control of transcription regulation in a gene-specific and tissue-specific manner. Chromatin status is one important mechanism, as DNA accessibility is a prerequisite for gene transcription.

 Post-translational covalent modifications of histone tails are involved in regulation of gene transcription, either directly by changing chromatin packing or through recruitment of other effector proteins to chromatin (chromatin ‘readers’; Fig. 1). Histone modifications are ‘written’ or ‘erased’ by histone-modifying enzymes (Kouzarides 2007). Menin is involved in trimethylation of lysine 4 on histone 3 (H3K4me3). This methylation mark is associated with activation of gene transcription (Kouzarides 2007). Histone acetylation is correlated with activation of gene transcription and deacetylation of histone tails with transcription repression. Epigenetic alterations, including deregulation of histone modifications contribute to cancer development (Chi et al. 2010). Deregulation of chromatin-modifying complexes by loss of menin is involved in MEN1 tumorigenesis.

Table 2

Cell systems used to study menin interaction partners

ReferenceProtein complexCell type (origin)Menin level
Hughes et al. (2004)Menin–MLL2293T (human embryonic kidney)Endogenous
Yokoyama et al. (2004)Menin–MLL1/2K562 (myelogenous leukemia)Endogenous
Milne et al. (2005)Menin–MLL1/2HeLa (human cervical cancer)Endogenous
Yokoyama & Cleary (2008)Menin–MLL1/2–PSIP1REH cells (human leukemia)Endogenous
Huang et al. (2012)Menin–MLL1–PSIP1Recombinant proteinIn vitro
293T (human embryonic kidney)Overexpressed
van Nuland et al. (2013))Menin–MLL1/2HeLa (human cervical cancer)Overexpressed
Agarwal et al. (1999)Menin–JUND293T (human embryonic kidney)Endogenous, overexpressed
Gobl et al. (1999)Menin–JUNDRecombinant proteinIn vitro
Mensah-Osman et al. (2011)Menin–JUNDAGS (human gastric adenocarcinoma)Overexpressed
Huang et al. (2012)Menin–JUNDRecombinant proteinBacterial expressed
293T (human embryonic kidney)Overexpressed
Kim et al. (2003)Menin–HDAC–mSin3A293T (human embryonic kidney)Overexpressed
Kaji et al. (2001)Menin–SMAD3Cos7 (monkey kidney)Overexpressed
Heppner et al. (2001)Menin–NFκB293 (human embryonic kidney)Endogenous, overexpressed
Sierra et al. (2006)Menin–β-cateninCRC (human colorectal cancer)Endogenous
Dreijerink et al. (2006)Menin–ERαRecombinant proteinIn vitro
Dreijerink et al. (2009)Menin–PPARγRecombinant proteinIn vitro
Gurung et al. (2013b)Menin–PRMT5293 (human embryonic kidney)Endogenous, overexpressed
Yang et al. (2013)Menin–SUV39H1293T (human embryonic kidney)Endogenous, overexpressed
Shi et al. (2013)Menin–Hlbx9MIN6 (mouse insulinoma)Endogenous, overexpressed

This table summarizes studies referred to in this review.

Figure 1
Figure 1

Chromatin structure and histone modifications. DNA is wrapped around octamers of histones into nucleosomes. Chromatin state is influenced by post-translational modifications of histone tails. These modifications are associated with chromatin accessibility for the effector proteins such as transcription factors and lead to an active or a repressed chromatin state. For simplicity, not all histone tails are represented in this figure. Adapted from the National Institutes of Health Common Fund Website, source: http://commonfund.nih.gov/epigenomics/figure.aspx, with permission.

Citation: Endocrine-Related Cancer 21, 3; 10.1530/ERC-13-0482

Menin as an epigenetic repressor of gene transcription

Menin associates with proteins in removing acetylation marks from histones (Gobl et al. 1999, Kim et al. 2003). These histone deacetylases (HDACs) form complexes with menin through the general co-repressor mSin3A (Kim et al. 2003; Fig. 2A). Deacetylation of histones at promoters of target genes is associated with downregulation of gene transcription. GAST (gastrin) was identified as a potential target of menin/mSin3A/HDAC complexes (Mensah-Osman et al. 2011).

Figure 2
Figure 2

Menin in epigenetic repression of gene transcription. (A) Menin transiently interacts with mSin3A and represses GAST transcription via recruitment of HDAC1, 2 and acetylation (ac) of histone tails. The protein complexes bind to the transcription factor (TF) JUND. (B) Menin transiently interacts with PRMT5 and represses gene transcription of GAS1 and GLI1 through dimethylation (me2) of histone H4R3. In this case, it is not known to which TF the protein complexes bind. (C) Menin transiently interacts with SUV39H1 and represses gene transcription of GBX2 through trimethylation of histone H3K9. In this case, it is not known to which TF the protein complexes bind.

Citation: Endocrine-Related Cancer 21, 3; 10.1530/ERC-13-0482

Recently, menin was shown to interact directly with protein arginine methyltransferase 5 (PRMT5), resulting in repression of the Hedgehog signaling pathway through increasing PRMT5-mediated dimethylation of arginine 3 on histone 4 (H4R3me2) at the GAS1 and GLI1 promoter (Gurung et al. 2013a,b; Fig. 2B). The Hedgehog signaling pathway is involved in various biological processes including (neuroendocrine) tumorigenesis (McMillan & Matsui 2012). Menin can be recruited to the promotor of the homeobox gene GBX2 through interaction with the histone lysine methyltransferase SUV39H1. This interaction induced H3K9 trimethylation at the gene promoter, providing the repressive chromatin environment for downregulation of GBX2 transcription (Yang et al. 2013; Fig. 2C).

Menin as an epigenetic activator of gene transcription

Menin stably associates with MLL1 and MLL2 (KMT2B)-containing protein complexes (Hughes et al. 2004, Yokoyama et al. 2004). The functional domain in MLL protein family members is the so-called SET domain that harbors histone methyltransferase activity for trimethylation toward lysine 4 of histone 3 (H3K4me3; Ruthenburg et al. 2007). H3K4me3 is associated with activation of gene transcription (Santos-Rosa et al. 2002, Guenther et al. 2007). MLL translocations leading to MLL1-fusion proteins are frequently seen in mixed lineage leukemia (Krivtsov & Armstrong 2007). In contrast to other menin interactors, the menin–MLL1/2 interactions are rather stable and have been detected in several cellular systems (Hughes et al. 2004, Yokoyama et al. 2004). The menin–MLL1/2 complexes induce trimethylation on H3K4, and menin disease-derived mutants fail to recruit histone methyltransferase activity (Hughes et al. 2004). Genome-wide analysis showed menin occupancy on promoters of many active genes, which is often accompanied with MLL1 or MLL2 and H3K4me3 (Scacheri et al. 2006, Agarwal & Jothi 2012). Menin–MLL1/2 complexes are positive regulators of several target genes, including genes of the HOX cluster (Hughes et al. 2004, Yokoyama et al. 2004) and cyclin-dependent kinase (CDK) inhibitor genes (Milne et al. 2005) (Fig. 3A). HOX genes are characterized by a conserved DNA sequence, the homeobox. They encode homeodomain-containing TFs, which are essential in cell differentiation and the body plan during embryogenesis. Several HOX genes are identified as direct menin–MLL1/2 targets, such as HOXA9, Hoxc6, and Hoxc8 (Hughes et al. 2004, Yokoyama et al. 2004, Huang et al. 2012). It was shown in pancreatic islet-like endocrine cells that HOX gene expression is regulated by menin through H3K4 methylation (Agarwal & Jothi 2012). Menin–MLL1 complexes stimulate the expression of CDKN1B and CDKN2C genes encoding p27Kip1 and p18Ink4c proteins respectively. Loss of function of menin or MLL1 resulted in downregulation of p27Kip1 and p18Ink4c and displayed effects on cell growth (Milne et al. 2005). p27Kip1 and p18Ink4c belong to two distinct families of CDK inhibitors which regulate cell-cycle progression (Besson et al. 2008). Reduced expression of these proteins contributes to tumor development in various tissues (Malumbres & Barbacid 2001).

Figure 3
Figure 3

Menin in epigenetic activation of gene transcription. (A) Menin interacts with MLL1/2, which results in trimethylation (me3) of histone H3K4 (H3K4me3) and activation of transcription of CDKN1B, CDKN2C, and HOX genes. The interacting transcription factor (TF) is not known in this case. (B) Menin–MLL1/2 complexes bind to nuclear receptors (NRs), induce H3K4me3, and activate transcription of NR-target genes. (C) Interaction of menin–MLL1/2 protein complexes with β-catenin activates c-Myc transcription through H3K4me3. The interacting TF is not known in this case.

Citation: Endocrine-Related Cancer 21, 3; 10.1530/ERC-13-0482

Recruitment of menin–chromatin modifying protein complexes to target genes

Proteins can be recruited to gene promoters through specific interactions with DNA sequence-specific TFs. Menin stably interacts with the DNA sequence-specific TF JUND (Agarwal et al. 1999, Huang et al. 2012; Fig. 2A). Several MEN1-derived missense mutants failed to bind JUND efficiently in vitro and their repressive effect on transcription was lost (Agarwal et al. 1999). Interactions between menin and other TFs are less stable than menin–JUND interactions. Menin can be tethered to DNA through the nuclear receptor (NR) for estrogen ERα, the NR peroxisome-proliferator-activated receptor γ (PPARγ), and the vitamin D3 receptor (Dreijerink et al. 2006, 2009; Fig. 3B). NRs have the ability to bind DNA directly and translate changes in hormone levels into alterations in gene transcription. Transcriptional activation through menin–NR interactions is associated with H3K4me3 upregulation (Dreijerink et al. 2006, 2009). Furthermore, menin–MLL1/2 complexes are transcriptional co-activators of the Wnt-signaling pathway. Together with the TF CTNNB1 (β-catenin), the menin–MLL2 complex was shown to be recruited to the enhancer of the oncogene c-Myc (Sierra et al. 2006; Fig. 3C). Menin interacts and regulates NFKB1 (NF-κB) TFs (Heppner et al. 2001). Transforming growth factor β (TGFβ) signaling causes inhibition of proliferation in various cell types. Menin interacts with the TGFβ-regulated TF SMAD3. Inactivation of menin in pituitary cells disrupted SMAD3 binding to DNA, thereby blocking TGFβ signaling (Kaji et al. 2001). Recently, TF Hlxb9 was shown to be a menin interaction partner specifically in mouse β-cells and to be involved in the regulation of β-cell proliferation rate and expression of insulin-modulating genes (Shi et al. 2013).

Besides DNA sequence-specific TF-mediated recruitment of menin–MLL1/2 complexes to target genes, interactions with chromatin-binding protein PC4 and SFRS1 interacting protein 1 (PSIP1) (also known as LEDGF/p75) are important for tethering these complexes to target genes. The transcription co-activator PSIP1 co-localizes with menin–MLL1 complexes at specific menin target genes, including HOXA9, CDKN1B, and CDKN2C (Yokoyama & Cleary 2008, Huang et al. 2012). The association of several menin mutants with PSIP1 was disrupted, resulting in reduced transcription of HOXA9 (Yokoyama & Cleary 2008).

Contribution of menin loss to NET development

Several studies have addressed the role of MEN1 in endocrine pancreatic cell function and proliferation. Absence of MEN1 does not seem to affect the initial pancreatic differentiation process from embryonic stem cells in vitro (Agarwal & Jothi 2012). β-cell specific disruption of MEN1 leads to the formation of insulinomas (Bertolino et al. 2003b, Crabtree et al. 2003, Biondi et al. 2004). α-cell-specific knockout of MEN1 was found to lead to transdifferentiation into insulin-producing cells and subsequent insulinoma development (Lu et al. 2010). Disturbance in epigenetic regulation of gene transcription is thought to contribute to MEN1-associated tumorigenesis. The most convincing evidence supporting this mechanism was reported recently (Lin et al. 2011). Mice with β-cell-specific knockout of MEN1 showed reduced tumor formation and increased survival in combination with gene knockout of the retinoblastoma-binding protein 2 (RBP2 also known as JARID1A, KDM5A), which is a histone demethylase for H3K4me2/3. This indicates that compensation of the loss of H3K4 trimethylation mark on certain target genes may restore the function of menin in pancreatic tumors. Identification of relevant menin target genes could provide further insights into the development of MEN1-related tumors. Currently, it is not clear how the tumor-suppressing roles of menin in cultured cells are related to suppression of MEN1-associated tumor development. HOX genes are important for the development of endocrine organs (Manley & Capecchi 1998). Comparison of HOX gene expression profiles in MEN1-associated parathyroid tumors and nonfamilial parathyroid tumors revealed differently expressed genes between these groups. This indicates a role for HOX genes in MEN1-associated parathyroid tumor development (Shen et al. 2008). This has not been shown for other NETs. Several animal studies support that menin target genes CDKN1B and CDKN2C are involved in endocrine tumorigenesis. p27kip1 or p18ink4c-deficient mice develop pituitary tumors and hyperplasia in multiple organs, including the thymus, without elevation in GH levels (Fero et al. 1996, Kiyokawa et al. 1996, Nakayama et al. 1996, Franklin et al. 1998). Strikingly, mice lacking both p27kip1 and p18ink4c developed hyperplasia and/or tumors predominantly in endocrine organs including the pancreas and duodenum. The tumor spectrum seen in these mice showed a remarkable overlap with the tumor spectrum seen in MEN1 patients (Franklin et al. 2000). Inactivating germline mutations in CDKN1B have been identified in patients with a MEN-like phenotype. Although, hyperparathyroidism and pituitary tumors are the most commonly described manifestations (Pellegata et al. 2006, Georgitsi et al. 2007), pNETs have also been described in association with CDKN1B mutations (Agarwal et al. 2009, Occhi et al. 2013). Based on these studies, a role for p27kip1 and p18ink4c in MEN1-related tumor development seems reasonable. Menin–MLL1/2 complexes inhibit proliferation of pancreatic islet cells in mice by promoting H3K4me3 and transcription of p27kip1 and p18ink4c (Karnik et al. 2005). Interestingly, p18ink4c and menin collaborate in repressing development and growth rate of mouse pNETs. This synergetic effect was not observed with p27kip1 (Bai et al. 2007). Studies focusing on p27kip1 protein and mRNA expression in pNETs from MEN1 patients show conflicting results (Milne et al. 2005, Lindberg et al. 2008, Occhi et al. 2013).

Tissue selectivity in MEN1-related tumorigenesis

Regarding the ubiquitous expression of menin, it is difficult to explain the tissue selectivity of tumorigenesis in MEN1 patients. Unfortunately, most studies focusing on menin interaction partners and its target genes are performed in nonendocrine cell lines (Table 2 and Supplementary Table 1, see section on supplementary data given at the end of this article). Menin acts as a tumor suppressor in endocrine organs, but it is an essential oncogenic cofactor in leukemogenesis (Yokoyama et al. 2005, Yokoyama & Cleary 2008). Understanding the predominance for endocrine tumor development resulting from MEN1 loss might help to develop targeted therapies for MEN1 patients. Several factors have been suggested as potential important players in the tissue selectivity of this endocrine tumor syndrome (Gracanin et al. 2009). Tissues may differ in their ability and requirement to compensate for the loss of one MEN1 allele (Gracanin et al. 2009). Physiological regulation of menin levels in response to increased insulin was shown to be important in adaptive β-cell proliferation during pregnancy in mice (Karnik et al. 2007). Intriguingly, mice with liver-specific loss of menin did not develop tumors (Scacheri et al. 2004). The expression levels of menin in lymphoblastic cell lines derived from MEN1 patients did not differ from healthy controls (Wautot et al. 2000) and downregulation of menin could activate the MEN1 promoter in a compensatory manner in non-endocrine cell lines (Zablewska et al. 2003). However, it has been suggested that menin haploinsufficiency through loss of one Men1 allele contributes to pNET development in mice (Crabtree et al. 2003, Lejonklou et al. 2012). In regard to tissue-specific regulation of menin expression, microRNAs are interesting candidates for further evaluation (Gracanin et al. 2009, Luzi & Brandi 2011). Menin interaction partners might be involved in the tissue-specific tumor formation in MEN1. For example, the TF HLXB9 was shown to be a β-cell-specific menin interaction partner (Shi et al. 2013). NRs are also potential candidates as they have tissue-specific functions.

Implications for further research

Although in the past decade significant progress has been made in understanding menin function, many questions remain. Its tumor-suppressive role in endocrine organs is not well understood and elucidation of underlying biology should be an important focus for future studies. Regarding the observed tissue selectivity in MEN1-related tumorigenesis, it is important to study menin–protein interactions and target genes in endocrine cell lines specifically. To date, most studies addressing menin interactions and target genes were performed in non-endocrine cell lines. Not only basic research projects but also translational studies in unbiased MEN1 patient cohorts are needed. These studies should clarify which molecular pathways involving menin actually contribute to MEN1 NET tumorigenesis and are clinically relevant. With regard to novel therapeutic strategies, the involvement of altered epigenetic regulation of gene expression resulting in MEN1 tumorigenesis is an interesting candidate for further evaluation. The development of compounds that interfere with epigenetic regulation of gene transcription has gained a lot of attention recently and such drugs have shown to have therapeutic potential in cancer treatment (Dawson & Kouzarides 2012). These findings highlight the importance of better insights into MEN1 tumorigenesis for the improvement of MEN1 patient care.

From a clinical point of view, identifying natural course and prognostic factors has been hampered by the rarity of the disease and generally low number of events regarding distant metastases and disease-related mortality. Therefore, it is important to follow large unselected cohorts over a long period of time, by national or even international collaboration.

When comparing natural history of MEN1-related NETs with their sporadic counterparts, insulinomas in MEN1 seem to be more aggressive, while natural history in MEN1-related gastrinomas seems to be similar to sporadic gastrinomas. Data on NF-pNETs and thoracic NETs are insufficient to permit comparisons. However, currently available evidence does not support MEN1-related NETs to be more indolent than sporadic NETs.

Among MEN1-related NETs, thNETs occur with low frequency and show a remarkable gender difference. Compared with other NETs, their prognosis is poor. These different epidemiologic and natural history characteristics cannot be explained with the currently available evidence and warrants further research.

Pulmonary carcinoids and NF-pNETs in MEN1 share the fact that they are more common than previously thought. Identification of these NETs will further increase in the coming decade due to increased sensitivity of imaging techniques and standardized screening. As little is known about the natural history of small NETs in MEN1, clinical significance of these findings remains to be determined. To assist clinical decision-making in this respect, studies with a long-term follow-up in unselected patient cohorts are needed.

All dpNETs are potentially malignant and dpNETs are the most important determinant of long-term survival in MEN1 patients. Although the estimated 10-year survival rate is 75%, it is important to remember that MEN1-patients are usually in their thirties when these tumors develop. Moreover, unless a total duodenopancreatectomy is performed, MEN1 patients are always at risk for developing new dpNETs and subsequent malignant transformation. This means that a satisfactory 10-year survival rate does not automatically equal normal life expectancy. Although, the percentage of MEN1 patients with dpNETs that develop distant metastases is small, prognosis is poor in this group. At present, apart from tumor size, there are no known clinical or tumor characteristics that reliably predict the development of distant metastases. This means that the impact of therapeutic interventions has to be weighed against the overall change of distant metastases and disease-related mortality. Identification of additional clinical and molecular prognostic factors in MEN1-related dpNETs should therefore be an important research focus. Factors known to be of prognostic value in sporadic dpNETs should be validated in MEN1 and new prognostic indicators sought for. These efforts should lead to early identification of tumors with an aggressive phenotype and subsequent individualized patient care based on risk stratification.

Supplementary data

This is linked to the online version of the paper at http://dx.doi.org/10.1530/ERC-13-0482.

Declaration of interest

G D Valk and M R Vriens are the receivers of an unrestricted grant from Ipsen.

Funding

H Th M Timmers was granted a NWO-Chemical Sciences TOP grant (700.57.302). K M A Dreijerink is supported by a fellowship from the Dutch Cancer Society (UU 2012 5370).

Acknowledgements

The authors thank Robert M Brucker for the design of the figures.

References

  • Abe T, Sato M, Okumura T, Shioyama Y, Kiyoshima M, Asato Y, Saito H, Iijima T, Amemiya R & Nagai H 2008 FDG PET/CT findings of thymic carcinoid and bronchial carcinoid in a patient with multiple neuroendocrine neoplasia type 1. Clinical Nuclear Medicine 33 778779. (doi:10.1097/RLU.0b013e318187efef).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Agarwal S & Jothi R 2012 Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors. PLoS ONE 7 e37952. (doi:10.1371/journal.pone.0037952).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Agarwal S, Kester M, Debelenko L, Heppner C, Emmert-Buck M, Skarulis M, Doppman J, Kim Y, Lubensky I & Zhuang Z et al. 1997 Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Human Molecular Genetics 6 11691175. (doi:10.1093/hmg/6.7.1169).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Agarwal S, Guru S, Heppner C, Erdos M, Collins R, Park S, Saggar S, Chandrasekharappa S, Collins F & Spiegel A et al. 1999 Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 96 143152. (doi:10.1016/S0092-8674(00)80967-8).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Agarwal S, Mateo C & Marx S 2009 Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. Journal of Clinical Endocrinology and Metabolism 94 18261834. (doi:10.1210/jc.2008-2083).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Aguayo S, Miller Y, Waldron JA Jr, Bogin R, Sunday M, Staton G Jr, Beam W & King T Jr 1992 Brief report: Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. New England Journal of Medicine 327 12851288. (doi:10.1056/NEJM199210293271806).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anlauf M, Perren A, Meyer CL, Schmid S, Saremaslani P, Kruse ML, Weihe E, Komminoth P, Heitz PU & Kloppel G 2005 Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas. Gastroenterology 128 11871198. (doi:10.1053/j.gastro.2005.01.058).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anlauf M, Garbrecht N, Henopp T, Schmitt A, Schlenger R, Raffel A, Krausch M, Gimm O, Eisenberger CF & Knoefel WT et al. 2006a Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features. World Journal of Gastroenterology 12 54405446.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anlauf M, Schlenger R, Perren A, Bauersfeld J, Koch CA, Dralle H, Raffel A, Knoefel WT, Weihe E & Ruszniewski P et al. 2006b Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. American Journal of Surgical Pathology 30 560574. (doi:10.1097/01.pas.0000194044.01104.25).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anlauf M, Bauersfeld J, Raffel A, Koch CA, Henopp T, Alkatout I, Schmitt A, Weber A, Kruse M & Braunstein S et al. 2009 Insulinomatosis: a multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia. American Journal of Surgical Pathology 33 339346. (doi:10.1097/PAS.0b013e3181874eca).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bai F, Pei XH, Nishikawa T, Smith MD & Xiong Y 2007 p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. Molecular and Cellular Biology 27 14951504. (doi:10.1128/MCB.01764-06).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ballard HS, Fame B & Hartsock RJ 1964 Familial multiple endocrine adenoma–peptic ulcer complex. Medicine 43 481516. (doi:10.1097/00005792-196407000-00003).

  • Bartsch DK, Langer P, Wild A, Schilling T, Celik I, Rothmund M & Nies C 2000 Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: surgery or surveillance? Surgery 128 958966. (doi:10.1067/msy.2000.109727).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bartsch DK, Fendrich V, Langer P, Celik I, Kann PH & Rothmund M 2005 Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Annals of Surgery 242 757764.(discussion 764–766) (doi:10.1097/01.sla.0000189549.51913.d8).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bertolino P, Radovanovic I, Casse H, Aguzzi A, Wang ZQ & Zhang CX 2003a Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs. Mechanisms of Development 120 549560. (doi:10.1016/S0925-4773(03)00039-X).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bertolino P, Tong WM, Herrera PL, Casse H, Zhang CX & Wang ZQ 2003b Pancreatic β-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Research 63 48364841.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Besson A, Dowdy SF & Roberts JM 2008 CDK inhibitors: cell cycle regulators and beyond. Developmental Cell 14 159169. (doi:10.1016/j.devcel.2008.01.013).

  • Biondi CA, Gartside MG, Waring P, Loffler KA, Stark MS, Magnuson MA, Kay GF & Hayward NK 2004 Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Molecular and Cellular Biology 24 31253131. (doi:10.1128/MCB.24.8.3125-3131.2004).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boddaert G, Grand B, Le Pimpec-Barthes F, Cazes A, Bertagna X & Riquet M 2012 Bronchial carcinoid tumors causing Cushing's syndrome: more aggressive behavior and the need for early diagnosis. Annals of Thoracic Surgery 94 18231829. (doi:10.1016/j.athoracsur.2012.07.022).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boers JE, den Brok JL, Koudstaal J, Arends JW & Thunnissen FB 1996 Number and proliferation of neuroendocrine cells in normal human airway epithelium. American Journal of Respiratory and Critical Care Medicine 154 758763. (doi:10.1164/ajrccm.154.3.8810616).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bosman FT, Carneiro F, Hruban RH & Theisse ND (Eds) 2010 In WHO Classification of Tumours of the Digestive System. Lyon: International Agency for Research on Cancer (IARC)

    • PubMed
    • Export Citation
  • Burgess JR, Greenaway TM, Parameswaran V, Challis DR, David R & Shepherd JJ 1998a Enteropancreatic malignancy associated with multiple endocrine neoplasia type 1: risk factors and pathogenesis. Cancer 83 428434. (doi:10.1002/(SICI)1097-0142(19980801)83:3<428::AID-CNCR10>3.0.CO;2-Y).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burgess JR, Greenaway TM & Shepherd JJ 1998b Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1. Journal of Internal Medicine 243 465470. (doi:10.1046/j.1365-2796.1998.00275.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, Oberg K, Werner S & Nordenskjöld M 1990 Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. PNAS 87 19681972. (doi:10.1073/pnas.87.5.1968).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cadiot G, Vuagnat A, Doukhan I, Murat A, Bonnaud G, Delemer B, Thiefin G, Beckers A, Veyrac M & Proye C et al. 1999 Prognostic factors in patients with Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1. Groupe d'Etude des Neoplasies Endocriniennes Multiples (GENEM and groupe de Recherche et d'Etude du Syndrome de Zollinger–Ellison (GRESZE). Gastroenterology 116 286293. (doi:10.1016/S0016-5085(99)70124-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cao C, Yan TD, Kennedy C, Hendel N, Bannon PG & McCaughan BC 2011 Bronchopulmonary carcinoid tumors: long-term outcomes after resection. Annals of Thoracic Surgery 91 339343. (doi:10.1016/j.athoracsur.2010.08.062).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cardillo G, Rea F, Lucchi M, Paul MA, Margaritora S, Carleo F, Marulli G, Mussi A, Granone P & Graziano P 2012 Primary neuroendocrine tumors of the thymus: a multicenter experience of 35 patients. Annals of Thoracic Surgery 94 241245.(discussion 245–246) (doi:10.1016/j.athoracsur.2012.03.062).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carty SE, Helm AK, Amico JA, Clarke MR, Foley TP, Watson CG & Mulvihill JJ 1998 The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 124 11061113.(discussion 1113–1114) (doi:10.1067/msy.1998.93107).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cavaco BM, Domingues R, Bacelar MC, Cardoso H, Barros L, Gomes L, Ruas MM, Agapito A, Garrão A & Pannett AA et al. 2002 Mutational analysis of Portuguese families with multiple endocrine neoplasia type 1 reveals large germline deletions. Clinical Endocrinology 56 465473. (doi:10.1046/j.1365-2265.2002.01505.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chandrasekharappa SC, Guru S, Manickam P, Olufemi S, Collins F, Emmert-Buck M, Debelenko L, Zhuang Z, Lubensky I & Liotta L et al. 1997 Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276 404407. (doi:10.1126/science.276.5311.404).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chi P, Allis CD & Wang GG 2010 Covalent histone modifications – miswritten, misinterpreted and mis-erased in human cancers. Nature Reviews. Cancer 10 457469. (doi:10.1038/nrc2876).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cougard P, Goudet P, Peix JL, Henry JF, Sarfati E, Proye C & Calender A 2000 Insulinomas in multiple endocrine neoplasia type 1. Report of a series of 44 cases by the Multiple Endocrine Neoplasia Study Group. Annales de Chirurgie 125 118123. (doi:10.1016/S0001-4001(00)00112-4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Crabtree JS, Scacheri PC, Ward JM, McNally SR, Swain GP, Montagna C, Hager JH, Hanahan D, Edlund H & Magnuson MA et al. 2003 Of mice and MEN1: insulinomas in a conditional mouse knockout. Molecular and Cellular Biology 23 60756085. (doi:10.1128/MCB.23.17.6075-6085.2003).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Crippa S, Zerbi A, Boninsegna L, Capitanio V, Partelli S, Balzano G, Pederzoli P, Di Carlo V & Falconi M 2012 Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Archives of Surgery 147 261266. (doi:10.1001/archsurg.2011.1843).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Crona J, Bjorklund P, Welin S, Kozlovacki G, Oberg K & Granberg D 2013 Treatment, prognostic markers and survival in thymic neuroendocrine tumours. A study from a single tertiary referral centre. Lung Cancer 79 289293. (doi:10.1016/j.lungcan.2012.12.001).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F & Daddi G 2004 Surgical treatment of neuroendocrine tumors of the lung. European Journal of Cardio-Thoracic Surgery 26 813817. (doi:10.1016/j.ejcts.2004.05.052).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Daddi N, Schiavon M, Filosso PL, Cardillo G, Ambrogi MC, De Palma A, Luzzi L, Bandiera A, Casali C & Ruffato A et al. Prognostic factors in a multicentre study of 247 atypical pulmonary carcinoids European Journal of Cardio-Thoracic Surgery 2013 doi:10.1093/ejcts/ezt470).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Davi MV, Boninsegna L, Dalle Carbonare L, Toaiari M, Capelli P, Scarpa A, Francia G & Falconi M 2011 Presentation and outcome of pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1 syndrome. Neuroendocrinology 94 5865. (doi:10.1159/000326164).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, Sheppard MN & Nicholson AG 2007 Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax 62 248252. (doi:10.1136/thx.2006.063065).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dawson MA & Kouzarides T 2012 Cancer epigenetics: from mechanism to therapy. Cell 150 1227. (doi:10.1016/j.cell.2012.06.013).

  • Debelenko LV, Brambilla E, Agarwal SK, Swalwell JI, Kester MB, Lubensky IA, Zhuang Z, Guru SC, Manickam P & Olufemi SE et al. 1997a Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Human Molecular Genetics 6 22852290. (doi:10.1093/hmg/6.13.2285).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Debelenko LV, Zhuang Z, Emmert-Buck MR, Chandrasekharappa SC, Manickam P, Guru SC, Marx SJ, Skarulis MC, Spiegel AM & Collins FS et al. 1997b Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors. Cancer Research 57 22382243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dickson PV, Rich TA, Xing Y, Cote GJ, Wang H, Perrier ND, Evans DB, Lee JE & Grubbs EG 2011 Achieving eugastrinemia in MEN1 patients: both duodenal inspection and formal lymph node dissection are important. Surgery 150 11431152. (doi:10.1016/j.surg.2011.09.028).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Divisi D, Di Tommaso S, Imbriglio G & Crisci R 2008 Multiple endocrine neoplasia with pulmonary localization: a new protocol of approach. Scientific World Journal 8 788792. (doi:10.1100/tsw.2008.103).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dong Q, Debelenko LV, Chandrasekharappa SC, Emmert-Buck MR, Zhuang Z, Guru SC, Manickam P, Skarulis M, Lubensky IA & Liotta LA et al. 1997 Loss of heterozygosity at 11q13: analysis of pituitary tumors, lung carcinoids, lipomas, and other uncommon tumors in subjects with familial multiple endocrine neoplasia type 1. Journal of Clinical Endocrinology and Metabolism 82 14161420. (doi:10.1210/jcem.82.5.3944).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Donow C, Pipeleers-Marichal M, Schroder S, Stamm B, Heitz PU & Kloppel G 1991 Surgical pathology of gastrinoma. Site, size, multicentricity, association with multiple endocrine neoplasia type 1, and malignancy. Cancer 68 13291334. (doi:10.1002/1097-0142(19910915)68:6<1329::AID-CNCR2820680624>3.0.CO;2-7).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dreijerink KM, Mulder KW, Winkler GS, Höppener JW, Lips CJ & Timmers HT 2006 Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Research 66 49294935. (doi:10.1158/0008-5472.CAN-05-4461).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dreijerink KM, Varier RA, van Beekum O, Jeninga EH, Hoppener JW, Lips CJ, Kummer JA, Kalkhoven E & Timmers HT 2009 The multiple endocrine neoplasia type 1 (MEN1) tumor suppressor regulates peroxisome proliferator-activated receptor γ-dependent adipocyte differentiation. Molecular and Cellular Biology 29 50605069. (doi:10.1128/MCB.01001-08).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dry J, Lebrigand H, Pradalier A, Leynadier F & Huguier M 1975 Familial bronchial carcinoid and polyendocrine adenomatosis. Annals de médicine interne 126 491496.

  • Duh QY, Hybarger CP, Geist R, Gamsu G, Goodman PC, Gooding GA & Clark OH 1987 Carcinoids associated with multiple endocrine neoplasia syndromes. American Journal of Surgery 154 142148. (doi:10.1016/0002-9610(87)90305-9).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ekeblad S, Skogseid B, Dunder K, Oberg K & Eriksson B 2008 Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clinical Cancer Research 14 77987803. (doi:10.1158/1078-0432.CCR-08-0734).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ellison EC, Sparks J, Verducci JS, Johnson JA, Muscarella P, Bloomston M & Melvin WS 2006 50-Year appraisal of gastrinoma: recommendations for staging and treatment. Journal of the American College of Surgeons 202 897905. (doi:10.1016/j.jamcollsurg.2006.02.013).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fabbri HC, Mello MP, Soardi FC, Esquiaveto-Aun AM, Oliveira DM, Denardi FC, Moura-Neto A, Garmes HM, Baptista MT & Matos PS et al. 2010 Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1. Arquivos Brasileiros de Endocrinologia e Metabologia 54 754760. (doi:10.1590/S0004-27302010000800016).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Farhangi M, Taylor J, Havey A & O'Dorisio TM 1987 Neuroendocrine (carcinoid) tumor of the lung and type I multiple endocrine neoplasia. Southern Medical Journal 80 14591462. (doi:10.1097/00007611-198711000-00033).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fendrich V, Langer P, Celik I, Bartsch DK, Zielke A, Ramaswamy A & Rothmund M 2006 An aggressive surgical approach leads to long-term survival in patients with pancreatic endocrine tumors. Annals of Surgery 244 845851.(discussion 852–853) (doi:10.1097/01.sla.0000246951.21252.60).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fendrich V, Habbe N, Celik I, Langer P, Zielke A, Bartsch DK & Rothmund M 2007 Operative management and long-term survival in patients with neuroendocrine tumors of the pancreas – experience with 144 patients. Deutsche Medizinische Wochenschrift 132 195200. (doi:10.1055/s-2007-959309).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V & Perlmutter RM et al. 1996 A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85 733744. (doi:10.1016/S0092-8674(00)81239-8).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ferolla P, Falchetti A, Filosso P, Tomassetti P, Tamburrano G, Avenia N, Daddi G, Puma F, Ribacchi R & Santeusanio F et al. 2005 Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. Journal of Clinical Endocrinology and Metabolism 90 26032609. (doi:10.1210/jc.2004-1155).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ferolla P, Daddi N, Urbani M, Semeraro A, Ribacchi R, Giovenali P, Ascani S, De Angelis V, Crino L & Puma F et al. 2009 Tumorlets, multicentric carcinoids, lymph–nodal metastases, and long-term behavior in bronchial carcinoids. Journal of Thoracic Oncology 4 383387. (doi:10.1097/JTO.0b013e318197f2e7).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M & Kramer MR 2001 Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 119 16471651. (doi:10.1378/chest.119.6.1647).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Finkelstein SD, Hasegawa T, Colby T & Yousem SA 1999 11q13 Allelic imbalance discriminates pulmonary carcinoids from tumorlets. A microdissection-based genotyping approach useful in clinical practice. American Journal of Pathology 155 633640. (doi:10.1016/S0002-9440(10)65159-0).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Franklin DS, Godfrey VL, Lee H, Kovalev GI, Schoonhoven R, Chen-Kiang S, Su L & Xiong Y 1998 CDK inhibitors p18INK4c and p27Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes and Development 12 28992911. (doi:10.1101/gad.12.18.2899).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Franklin DS, Godfrey VL, O'Brien DA, Deng C & Xiong Y 2000 Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Molecular and Cellular Biology 20 61476158. (doi:10.1128/MCB.20.16.6147-6158.2000).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Friedman E, Sakaguchi K, Bale A, Falchetti A, Streeten E, Zimering M, Weinstein L, McBride W, Nakamura Y & Brandi M et al. 1989 Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. New England Journal of Medicine 321 1057. (doi:10.1056/NEJM198907273210402).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fukai I, Masaoka A, Fujii Y, Yamakawa Y, Yokoyama T, Murase T & Eimoto T 1999 Thymic neuroendocrine tumor (thymic carcinoid): a clinicopathologic study in 15 patients. Annals of Thoracic Surgery 67 208211. (doi:10.1016/S0003-4975(98)01063-7).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gal AA, Kornstein MJ, Cohen C, Duarte IG, Miller JI & Mansour KA 2001 Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study. Annals of Thoracic Surgery 72 11791182. (doi:10.1016/S0003-4975(01)03032-6).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Garby L, Caron P, Claustrat F, Chanson P, Tabarin A, Rohmer V, Arnault G, Bonnet F, Chabre O & Christin-Maitre S et al. 2012 Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone-releasing hormone (GHRH): a French nationwide series of 21 cases. Journal of Clinical Endocrinology and Metabolism 97 20932104. (doi:10.1210/jc.2011-2930).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Garcia-Yuste M, Matilla JM, Cueto A, Paniagua JM, Ramos G, Canizares MA & Muguruza I 2007 Typical and atypical carcinoid tumours: analysis of the experience of the Spanish Multi-centric Study of Neuroendocrine Tumours of the Lung. European Journal of Cardio-Thoracic Surgery 31 192197. (doi:10.1016/j.ejcts.2006.11.031).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gaur P, Leary C & Yao JC 2010 Thymic neuroendocrine tumors: a SEER database analysis of 160 patients. Annals of Surgery 251 11171121. (doi:10.1097/SLA.0b013e3181dd4ec4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Geerdink EA, Van der Luijt RB & Lips CJ 2003 Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening? European Journal of Endocrinology 149 577582. (doi:10.1530/eje.0.1490577).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Georgitsi M, Raitila A, Karhu A, van der Luijt RB, Aalfs CM, Sane T, Vierimaa O, Mäkinen MJ, Tuppurainen K & Paschke R et al. 2007 Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. Journal of Clinical Endocrinology and Metabolism 92 33213325. (doi:10.1210/jc.2006-2843).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gibril F, Venzon DJ, Ojeaburu JV, Bashir S & Jensen RT 2001 Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. Journal of Clinical Endocrinology and Metabolism 86 52825293. (doi:10.1210/jcem.86.11.8011).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gibril F, Chen YJ, Schrump DS, Vortmeyer A, Zhuang Z, Lubensky IA, Reynolds JC, Louie A, Entsuah LK & Huang K et al. 2003 Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. Journal of Clinical Endocrinology and Metabolism 88 10661081. (doi:10.1210/jc.2002-021314).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Giudici F, Nesi G, Brandi ML & Tonelli F 2012 Surgical management of insulinomas in multiple endocrine neoplasia type 1. Pancreas 41 547553. (doi:10.1097/MPA.0b013e3182374e08).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gobl AE, Berg M, Lopez-Egido JR, Oberg K, Skogseid B & Westin G 1999 Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism. Biochimica et Biophysica Acta 1447 5156. (doi:10.1016/S0167-4781(99)00132-3).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goretzki P, Starke A, Lammers B, Schwarz K & Roher HD 2010 Pancreatic hyperinsulinism – changes of the clinical picture and importance of differences in sporadic disease course (experience with 144 patients operated in the period 1986–2009). Zentralblatt für Chirurgie 135 218225. (doi:10.1055/s-0030-1247316).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gortz B, Roth J, Krahenmann A, de Krijger RR, Muletta-Feurer S, Rutimann K, Saremaslani P, Speel EJ, Heitz PU & Komminoth P 1999 Mutations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms. American Journal of Pathology 154 429436. (doi:10.1016/S0002-9440(10)65289-3).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goudet P, Murat A, Cardot-Bauters C, Emy P, Baudin E, du Boullay Choplin H, Chapuis Y, Kraimps JL, Sadoul JL & Tabarin A et al. 2009 Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines). World Journal of Surgery 33 11971207. (doi:10.1007/s00268-009-9980-y).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goudet P, Murat A, Binquet C, Cardot-Bauters C, Costa A, Ruszniewski P, Niccoli P, Menegaux F, Chabrier G & Borson-Chazot F et al. 2010 Risk factors and causes of death in MEN1 disease. A GTE (Groupe d'Etude des Tumeurs Endocrines) cohort study among 758 patients. World Journal of Surgery 34 249255. (doi:10.1007/s00268-009-0290-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goudet P, Bonithon-Kopp C, Murat A, Ruszniewski P, Niccoli P, Menegaux F, Chabrier G, Borson-Chazot F, Tabarin A & Bouchard P et al. 2011 Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines. European Journal of Endocrinology 165 97105. (doi:10.1530/EJE-10-0950).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gracanin A, Dreijerink KM, van der Luijt RB, Lips CJ & Hoppener JW 2009 Tissue selectivity in multiple endocrine neoplasia type 1-associated tumorigenesis. Cancer Research 69 63716374. (doi:10.1158/0008-5472.CAN-09-0678).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grama D, Skogseid B, Wilander E, Eriksson B, Martensson H, Cedermark B, Ahren B, Kristofferson A, Oberg K & Rastad J et al. 1992 Pancreatic tumors in multiple endocrine neoplasia type 1: clinical presentation and surgical treatment. World Journal of Surgery 16 611618.(discussion 618–619) (doi:10.1007/BF02067335).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guenther M, Levine S, Boyer L, Jaenisch R & Young R 2007 A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130 7788. (doi:10.1016/j.cell.2007.05.042).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS & Chandrasekharappa SC 1998 Menin, the product of the MEN1 gene, is a nuclear protein. PNAS 95 16301634. (doi:10.1073/pnas.95.4.1630).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gurung B, Feng Z & Hua X 2013a Menin directly represses expression of Gli1 independent of the canonical Hedgehog signaling pathway. Molecular Cancer Research 11 12151222. (doi:10.1158/1541-7786.MCR-13-0170).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gurung B, Feng Z, Iwamoto DV, Thiel A, Jin G, Fan CM, Ng JM, Curran T & Hua X 2013b Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome. Cancer Research 73 26502658. (doi:10.1158/0008-5472.CAN-12-3158).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hamaji M, Allen MS, Cassivi SD, Nichols FC III, Wigle DA, Deschamps C & Shen KR 2012 The role of surgical management in recurrent thymic tumors. Annals of Thoracic Surgery 94 247254.(discussion 254) (doi:10.1016/j.athoracsur.2012.02.092).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Heppner C, Bilimoria KY, Agarwal SK, Kester M, Whitty LJ, Guru SC, Chandrasekharappa SC, Collins FS, Spiegel AM & Marx SJ et al. 2001 The tumor suppressor protein menin interacts with NF-κB proteins and inhibits NF-κB-mediated transactivation. Oncogene 20 49174925. (doi:10.1038/sj.onc.1204529).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hessman O, Lindberg D, Skogseid B, Carling T, Hellman P, Rastad J, Akerström G & Westin G 1998 Mutation of the multiple endocrine neoplasia type 1 gene in nonfamilial, malignant tumors of the endocrine pancreas. Cancer Research 58 377379.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hessman O, Lindberg D, Einarsson A, Lillhager P, Carling T, Grimelius L, Eriksson B, Akerstrom G, Westin G & Skogseid B 1999 Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN 1-associated pancreatic endocrine tumors. Genes, Chromosomes & Cancer 26 258264. (doi:10.1002/(SICI)1098-2264(199911)26:3<258::AID-GCC11>3.0.CO;2-2).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hessman O, Skogseid B, Westin G & Akerstrom G 2001 Multiple allelic deletions and intratumoral genetic heterogeneity in MEN1 pancreatic tumors. Journal of Clinical Endocrinology and Metabolism 86 13551361. (doi:10.1210/jcem.86.3.7332).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X & Lei M 2012 The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482 542546. (doi:10.1038/nature10806).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hughes C, Rozenblatt-Rosen O, Milne T, Copeland T, Levine S, Lee J, Hayes D, Shanmugam K, Bhattacharjee A & Biondi C et al. 2004 Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Molecular Cell 13 587597. (doi:10.1016/S1097-2765(04)00081-4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ikeo Y, Sakurai A, Suzuki R, Zhang MX, Koizumi S, Takeuchi Y, Yumita W, Nakayama J & Hashizume K 2000 Proliferation-associated expression of the MEN1 gene as revealed by in situ hybridization: possible role of the menin as a negative regulator of cell proliferation under DNA damage. Laboratory Investigation 80 797804. (doi:10.1038/labinvest.3780084).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imamura M, Komoto I, Ota S, Hiratsuka T, Kosugi S, Doi R, Awane M & Inoue N 2011 Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients. World Journal of Gastroenterology 17 13431353. (doi:10.3748/wjg.v17.i10.1343).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ito T, Igarashi H, Uehara H, Berna MJ & Jensen RT 2013 Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger–Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine 92 135181. (doi:10.1097/MD.0b013e3182954af1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jensen RT 1998 Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1. Journal of Internal Medicine 243 477488. (doi:10.1046/j.1365-2796.1998.00281.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL & Choti MA et al. 2011 DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331 11991203. (doi:10.1126/science.1200609).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jin S, Mao H, Schnepp RW, Sykes SM, Silva AC, D'Andrea AD & Hua X 2003 Menin associates with FANCD2, a protein involved in repair of DNA damage. Cancer Research 63 42044210.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaji H, Canaff L, Lebrun JJ, Goltzman D & Hendy GN 2001 Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type β signaling. PNAS 98 38373842. (doi:10.1073/pnas.061358098).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kann PH, Balakina E, Ivan D, Bartsch DK, Meyer S, Klose KJ, Behr T & Langer P 2006 Natural course of small, asymptomatic neuroendocrine pancreatic tumours in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study. Endocrine-Related Cancer 13 11951202. (doi:10.1677/erc.1.01220).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Karges W, Schaaf L, Dralle H & Boehm BO 2000 Concepts for screening and diagnostic follow-up in multiple endocrine neoplasia type 1 (MEN1). Experimental and Clinical Endocrinology & Diabetes 108 334340. (doi:10.1055/s-2000-8146).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Karnik SK, Hughes CM, Gu X, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M & Kim SK 2005 Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. PNAS 102 1465914664. (doi:10.1073/pnas.0503484102).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Karnik SK, Chen H, McLean GW, Heit JJ, Gu X, Zhang AY, Fontaine M, Yen MH & Kim SK 2007 Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science 318 806809. (doi:10.1126/science.1146812).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim H, Lee J, Cho E, Liu J & Youn H 2003 Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A–histone deacetylase complex. Cancer Research 63 61356139.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday A, Frohman L & Koff A 1996 Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85 721732. (doi:10.1016/S0092-8674(00)81238-6).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kloppel G, Willemer S, Stamm B, Hacki WH & Heitz PU 1986 Pancreatic lesions and hormonal profile of pancreatic tumors in multiple endocrine neoplasia type I. An immunocytochemical study of nine patients. Cancer 57 18241832. (doi:10.1002/1097-0142(19860501)57:9<1824::AID-CNCR2820570920>3.0.CO;2-Q).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Knudson A 1971 Mutation and cancer: statistical study of retinoblastoma. PNAS 68 820823. (doi:10.1073/pnas.68.4.820).

  • Kondo K & Monden Y 2003 Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Annals of Thoracic Surgery 76 878884.(discussion 884–885) (doi:10.1016/S0003-4975(03)00555-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kouvaraki MA, Lee JE, Shapiro SE, Gagel RF, Sherman SI, Sellin RV, Cote GJ & Evans DB 2002 Genotype–phenotype analysis in multiple endocrine neoplasia type 1. Archives of Surgery 137 641647. (doi:10.1001/archsurg.137.6.641).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kouvaraki MA, Shapiro SE, Cote GJ, Lee JE, Yao JC, Waguespack SG, Gagel RF, Evans DB & Perrier ND 2006 Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World Journal of Surgery 30 643653. (doi:10.1007/s00268-006-0360-y).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kouzarides T 2007 Chromatin modifications and their function. Cell 128 693705. (doi:10.1016/j.cell.2007.02.005).

  • Krivtsov A & Armstrong S 2007 MLL translocations, histone modifications and leukaemia stem-cell development. Nature Reviews. Cancer 7 823833. (doi:10.1038/nrc2253).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Laat JM, Tham E, Pieterman CR, Vriens MR, Dorresteijn JA, Bots ML, Nordenskjold M, van der Luijt RB & Valk GD 2012 Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors. European Journal of Endocrinology 167 181187. (doi:10.1530/EJE-12-0210).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lairmore TC, Chen VY, DeBenedetti MK, Gillanders WE, Norton JA & Doherty GM 2000 Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Annals of Surgery 231 909918. (doi:10.1097/00000658-200006000-00016).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Larsson C, Skogseid B, Oberg K, Nakamura Y & Nordenskjöld M 1988 Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332 8587. (doi:10.1038/332085a0).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Le Bodic MF, Heymann MF, Lecomte M, Berger N, Berger F, Louvel A, De Micco C, Patey M, De Mascarel A & Burtin F et al. 1996 Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. American Journal of Surgical Pathology 20 13781384. (doi:10.1097/00000478-199611000-00009).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lejonklou MH, Barbu A, Stalberg P & Skogseid B 2012 Accelerated proliferation and differential global gene expression in pancreatic islets of five-week-old heterozygous Men1 mice: Men1 is a haploinsufficient suppressor. Endocrinology 153 25882598. (doi:10.1210/en.2011-1924).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lemmens I, Van de Ven W, Kas K, Zhang C, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J & Lenoir G et al. 1997 Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Human Molecular Genetics 6 11771183. (doi:10.1093/hmg/6.7.1177).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lemos MC & Thakker RV 2008 Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Human Mutation 29 2232. (doi:10.1002/humu.20605).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Levy-Bohbot N, Merle C, Goudet P, Delemer B, Calender A, Jolly D, Thiefin G & Cadiot G 2004 Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterologie Clinique et Biologique 28 10751081. (doi:10.1016/S0399-8320(04)95184-6).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP & Zou MR et al. 2011 Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. PNAS 108 1337913386. (doi:10.1073/pnas.1110104108).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lindberg D, Akerstrom G & Westin G 2008 Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours. Clinical Endocrinology 68 271277. (doi:10.1111/j.1365-2265.2007.03034.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lopez CL, Waldmann J, Fendrich V, Langer P, Kann PH & Bartsch DK 2011 Long-term results of surgery for pancreatic neuroendocrine neoplasms in patients with MEN1. Langenbeck's Archives of Surgery 396 11871196. (doi:10.1007/s00423-011-0828-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lopez CL, Falconi M, Waldmann J, Boninsegna L, Fendrich V, Goretzki PK, Langer P, Kann PH, Partelli S & Bartsch DK 2013 Partial pancreaticoduodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine neoplasia type 1. Annals of Surgery 257 308314. (doi:10.1097/SLA.0b013e3182536339).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lourenco-Jr DM, Toledo RA, Coutinho FL, Margarido LC, Siqueira SA, dos Santos MA, Montenegro FL, Machado MC & Toledo SP 2007 The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1. Clinics 62 465476. (doi:10.1590/S1807-59322007000400014).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lowney JK, Frisella MM, Lairmore TC & Doherty GM 1998 Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: correlation with primary tumor size. Surgery 124 10431048.(discussion 1048–1049) (doi:10.1067/msy.1998.92561).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lu J, Herrera PL, Carreira C, Bonnavion R, Seigne C, Calender A, Bertolino P & Zhang CX 2010 Alpha cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development. Gastroenterology 138 19541965. (doi:10.1053/j.gastro.2010.01.046).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lubensky I, Debelenko L, Zhuang Z, Emmert-Buck M, Dong Q, Chandrasekharappa S, Guru S, Manickam P, Olufemi S & Marx S et al. 1996 Allelic deletions on chromosome 11q13 in multiple tumors from individual MEN1 patients. Cancer Research 56 52725278.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Luzi E & Brandi ML 2011 Are microRNAs involved in the endocrine-specific pattern of tumorigenesis in multiple endocrine neoplasia type 1? Endocrine Practice 17 (Suppl 3) 5863. (doi:10.4158/EP11062.RA).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Luzi E, Marini F, Giusti F, Galli G, Cavalli L & Brandi ML 2012 The negative feedback-loop between the oncomir Mir-24-1 and menin modulates the Men1 tumorigenesis by mimicking the “Knudson's second hit”. PLoS ONE 7 e39767. (doi:10.1371/journal.pone.0039767).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Malumbres M & Barbacid M 2001 To cycle or not to cycle: a critical decision in cancer. Nature Reviews. Cancer 1 222231. (doi:10.1038/35106065).

  • Manley NR & Capecchi MR 1998 Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. Developmental Biology 195 115. (doi:10.1006/dbio.1997.8827).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Marx S, Spiegel AM, Skarulis MC, Doppman JL, Collins FS & Liotta LA 1998 Multiple endocrine neoplasia type 1: clinical and genetic topics. Annals of Internal Medicine 129 484494. (doi:10.7326/0003-4819-129-6-199809150-00011).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Matkar S, Thiel A & Hua X 2013 Menin: a scaffold protein that controls gene expression and cell signaling. Trends in Biochemical Sciences 38 394402. (doi:10.1016/j.tibs.2013.05.005).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Matsuda KM, Nobrega R, Quezado M, Schrump DS & Filie AC 2010 Melanocytic bronchopulmonary carcinoid tumor in a patient with multiple endocrine neoplasia syndrome type 1: a case report with emphasis on intraoperative cytological findings. Diagnostic Cytopathology 38 669674. (doi:10.1002/dc.21296).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McMillan R & Matsui W 2012 Molecular pathways: the Hedgehog signaling pathway in cancer. Clinical Cancer Research 18 48834888. (doi:10.1158/1078-0432.CCR-11-2509).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Melvin WS, Johnson JA, Sparks J, Innes JT & Ellison EC 1993 Long-term prognosis of Zollinger–Ellison syndrome in multiple endocrine neoplasia. Surgery 114 11831188.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mensah-Osman EJ, Veniaminova NA & Merchant JL 2011 Menin and JunD regulate gastrin gene expression through proximal DNA elements. American Journal of Physiology. Gastrointestinal and Liver Physiology 301 G783G790. (doi:10.1152/ajpgi.00160.2011).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, Schnepp RW, Krankel C, Livolsi VA & Gibbs D et al. 2005 Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. PNAS 102 749754. (doi:10.1073/pnas.0408836102).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Montero C, Sanjuan P, Fernandez Mdel M, Vidal I, Verea H & Cordido F 2010 Bronchial carcinoid and type 1 multiple endocrine neoplasia syndrome. A case report. Archivos de Bronconeumología 46 559561. (doi:10.1016/S1579-2129(11)60009-8).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Montpreville VT, Macchiarini P & Dulmet E 1996 Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. Journal of Thoracic and Cardiovascular Surgery 111 134141. (doi:10.1016/S0022-5223(96)70409-9).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moran CA & Suster S 2000a Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. American Journal of Clinical Pathology 114 100110. (doi:10.1309/3PDN-PMT5-EQTM-H0CD).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moran CA & Suster S 2000b Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma, A clinicopathologic and immunohistochemical study of 11 cases. American Journal of Clinical Pathology 113 345350. (doi:10.1309/Q01U-60BL-VEV4-TWR1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Murai MJ, Chruszcz M, Reddy G, Grembecka J & Cierpicki T 2011 Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein. Journal of Biological Chemistry 286 3174231748. (doi:10.1074/jbc.M111.258186).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Murat A, Heymann MF, Bernat S, Dupas B, Delajartre AY, Calender A, Despins P, Michaud JL, Giraud S & Le Bodic MF et al. 1997 Thymic and bronchial neuroendocrine tumors in multiple endocrine neoplasia type 1. GENEM1. Presse Médicale 26 16161621.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Naalsund A, Rostad H, Strom EH, Lund MB & Strand TE 2011 Carcinoid lung tumors – incidence, treatment and outcomes: a population-based study. European Journal of Cardio-Thoracic Surgery 39 565569. (doi:10.1016/j.ejcts.2010.08.036).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I & Loh DY 1996 Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85 707720. (doi:10.1016/S0092-8674(00)81237-4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nikfarjam M, Warshaw AL, Axelrod L, Deshpande V, Thayer SP, Ferrone CR & Fernandez-del Castillo C 2008 Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Annals of Surgery 247 165172. (doi:10.1097/SLA.0b013e31815792ed).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Norton JA, Fraker DL, Alexander HR, Venzon DJ, Doppman JL, Serrano J, Goebel SU, Peghini PL, Roy PK & Gibril F et al. 1999 Surgery to cure the Zollinger–Ellison syndrome. New England Journal of Medicine 341 635644. (doi:10.1056/NEJM199908263410902).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F & Jensen RT 2001 Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger–Ellison syndrome. Annals of Surgery 234 495505.(discussion 505–506) (doi:10.1097/00000658-200110000-00009).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van Nuland R, Smits AH, Pallaki P, Jansen PWTC, Vermeulen M & Timmers HTM 2013 Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. Molecular and Cellular Biology 33 20672077. (doi:10.1128/MCB.01742-12).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Occhi G, Regazzo D, Trivellin G, Boaretto F, Ciato D, Bobisse S, Ferasin S, Cetani F, Pardi E & Korbonits M et al. 2013 A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genetics 9 e1003350. (doi:10.1371/journal.pgen.1003350).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Okoye CC, Jablons DM, Jahan TM, Kukreja J, Cardozo S & Yom SS Divergent management strategies for typical versus atypical carcinoid tumors of the thoracic cavity American Journal of Clinical Oncology 2013 doi:10.1097/COC.0b013e31827a7f6d).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pannett AA & Thakker RV 2001 Somatic mutations in MEN type 1 tumors, consistent with the Knudson “two-hit” hypothesis. Journal of Clinical Endocrinology and Metabolism 86 43714374. (doi:10.1210/jcem.86.9.7844).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pellegata N, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Höfler H, Fend F, Graw J & Atkinson M 2006 Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. PNAS 103 1555815563. (doi:10.1073/pnas.0603877103).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Perren A, Anlauf M, Henopp T, Rudolph T, Schmitt A, Raffel A, Gimm O, Weihe E, Knoefel WT & Dralle H et al. 2007 Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas. Journal of Clinical Endocrinology and Metabolism 92 11181128. (doi:10.1210/jc.2006-1944).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Petzmann S, Ullmann R, Klemen H, Renner H & Popper HH 2001 Loss of heterozygosity on chromosome arm 11q in lung carcinoids. Human Pathology 32 333338. (doi:10.1053/hupa.2001.22762).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pieterman CR, Schreinemakers JM, Koppeschaar HP, Vriens MR, Rinkes IH, Zonnenberg BA, van der Luijt RB & Valk GD 2009 Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome. Clinical Endocrinology 70 575581. (doi:10.1111/j.1365-2265.2008.03324.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pipeleers-Marichal M, Somers G, Willems G, Foulis A, Imrie C, Bishop AE, Polak JM, Hacki WH, Stamm B & Heitz PU et al. 1990 Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger–Ellison syndrome. New England Journal of Medicine 322 723727. (doi:10.1056/NEJM199003153221103).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pipeleers-Marichal M, Donow C, Heitz PU & Kloppel G 1993 Pathologic aspects of gastrinomas in patients with Zollinger–Ellison syndrome with and without multiple endocrine neoplasia type I. World Journal of Surgery 17 481488. (doi:10.1007/BF01655107).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Proye C, Stalnikiewicz G, Wemeau JL, Porchet N, D'Herbomez M, Maunoury V & Bauters C 2004 Genetically-driven or supposed genetic-related insulinomas in adults: validation of the surgical strategy proposed by the A.F.C.E./G.E.N.E.M. Annales d'Endocrinologie 65 149161. (doi:10.1016/S0003-4266(04)95663-6).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pusceddu S, Catena L, Valente M, Buzzoni R, Formisano B, Del Vecchio M, Ducceschi M, Tavecchio L, Fabbri A & Bajetta E 2010 Long-term follow up of patients affected by pulmonary carcinoid at the Istituto Nazionale Tumori of Milan: a retrospective analysis. Journal of Thoracic Disease 2 1620.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M & Komminoth P et al. 2006 TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Archiv 449 395401. (doi:10.1007/s00428-006-0250-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, Capella C, Caplin M, Couvelard A & Doglioni C et al. 2012 TNM staging of neoplasms of the endocrine pancreas: results from a large International Cohort Study. Journal of the National Cancer Institute 104 764777. (doi:10.1093/jnci/djs208).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rosai J & Higa E 1972 Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer 29 10611074. (doi:10.1002/1097-0142(197204)29:4<1061::AID-CNCR2820290456>3.0.CO;2-3).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rosai J, Higa E & Davie J 1972 Mediastinal endocrine neoplasm in patients with multiple endocrine adenomatosis. A previously unrecognized association. Cancer 29 10751083. (doi:10.1002/1097-0142(197204)29:4<1075::AID-CNCR2820290457>3.0.CO;2-O).

    • PubMed