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Asterios Karagiannis, Dimitri P Mikhailidis, Vasilios G Athyros, and Faidon Harsoulis

Pheochromocytomas (PHEOs) are rare neoplasms that produce catecholamines and usually arise from the adrenal medulla and are considered to be an adrenal paraganglioma (PGL). Closely related tumors of extraadrenal sympathetic and parasympathetic paraganglia are classified as extraadrenal PGLs. Most PHEOs are sporadic, but a significant percentage (∼25%) may be found in patients with germline mutations of genes predisposing to the development of von Hippel–Lindau disease, neurofibromatosis 1, multiple endocrine neoplasia type 1 (MEN1) and 2 (MEN2), and the PGL/PHEOs syndrome, based on the described mutations of the genes for succinate dehydrogenase subunit D (SDHD), B (SDHB), and C (SDHC). As one out of four PHEOs turns out to be a hereditary clinical entity, screening for genetic alterations is important, as it provides useful information for a rational diagnostic approach and management. This review discusses the genetics, the pathophysiology of hypertension, the clinical picture, the biochemical and imaging diagnosis, and the preferred therapeutic approach for PGLs/PHEOs. Furthermore, it emphasizes the need for genetic testing in cases with apparently sporadic PHEOs.

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Eamonn R Maher

In this issue of Endocrine-Related Cancer, Toledo et al. report the identification of activating mutations in the HIF2 (EPAS1) transcription factor in a subset of sporadic pheochromocytomas and paragangliomas. These findings add significantly to an evolving and complex story of the role of hypoxic gene response pathways in human endocrine neoplasia.

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Stephen J Marx

Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P<0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P<0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P<0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia.

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Nader Hussein, JieLi Lu, Huguette Casse, Sandra Fontanière, Anne-Marie Morera, Séverine Mazaud Guittot, Alain Calender, Nathalie Di Clemente, and Chang X Zhang

Multiple endocrine neoplasia type 1 (MEN1) results from the mutation of the predisposing gene, MEN1. Heterozygous Men1 mutant mice previously generated by several laboratories, including ours, mimic largely MEN1 pathology. Interestingly, our heterozygous Men1 mutant mice exhibit not only the endocrine tumours commonly seen in MEN1 patients, but also Leydig cell tumours (LCT) with high frequency, accompanied systematically by loss of the wild-type Men1 allele. As there exists a similarity of tumour phenotype between these mice and those mutated for the components of anti-Mullerian hormone (AMH)/bone morphogenic protein (BMP) pathway belonging to transforming growth factor-β (TGF-β) family, we investigated the expression and the activity of this pathway, known to have an important biological role in Leydig cells. Here, we report that the expression of AMH receptor type 2 is reduced in Men1 LCTs. Both immunostaining and western blot analyses also demonstrate a markedly decreased nuclear expression of Smad1, 3, 4 and 5 in the tumours. More interestingly, we show that the reconstituted menin expression in Men1-deficient Leydig cells derived from LCTs can significantly increase the transcriptional activity of a BMP pathway target promoter, XVent2. Furthermore, we found that the expression of p18, p27 and cyclin dependant kinase 4 (Cdk4), targets of TGF-β pathways, is altered in the Leydig cell lesions. Our data provide the evidence of the deregulation of AMH/BMP and TGF-β pathways in mouse Men1 LCTs, highlighting their involvement in tumorigenesis of Leydig cells due to Men1 inactivation.

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H-C Jennifer Shen, Jennifer E Rosen, Lauren M Yang, Sharon A Savage, A Lee Burns, Carmen M Mateo, Sunita K Agarwal, Settara C Chandrasekharappa, Allen M Spiegel, Francis S Collins, Stephen J Marx, and Steven K Libutti

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome caused by mutations in the MEN1 tumor suppressor gene. Loss of the functional second copy of the MEN1 gene causes individuals to develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and pancreas. While it is clear that the protein encoded by MEN1, menin, suppresses endocrine tumors, its biochemical functions and direct downstream targets remain unclear. Recent studies have suggested that menin may act as a scaffold protein to coordinate gene transcription, and that menin is an oncogenic cofactor for homeobox (HOX) gene expression in hematopoietic cancer. The role of HOX genes in adult cell differentiation is still obscure, but growing evidence suggests that they may play important roles in the development of cancer. Therefore, we hypothesized that specific HOX genes were regulated by menin in parathyroid tumor development. Utilizing quantitative TaqMan RT-PCR, we compared expression profiles of the 39 HOX genes in human familial MEN1 (fMEN1) parathyroid tumors and sporadic parathyroid adenomas with normal samples. We identified a large set of 23 HOX genes whose deregulation is specific for fMEN1 parathyroid tumors, and only 5 HOX genes whose misexpression are specific for sporadic parathyroid tumor development. These findings provide the first evidence that loss of the MEN1 tumor suppressor gene is associated with deregulation of specific HOX gene expression in the development of familial human parathyroid tumors. Our results strongly reinforce the idea that abnormal expression of developmental HOX genes can be critical in human cancer progression.

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Maria A Tichomirowa, Misu Lee, Anne Barlier, Adrian F Daly, Ilaria Marinoni, Marie-Lise Jaffrain-Rea, Luciana A Naves, Patrice Rodien, Vincent Rohmer, Fabio Rueda Faucz, Philippe Caron, Bruno Estour, Pierre Lecomte, Françoise Borson-Chazot, Alfred Penfornis, Maria Yaneva, Mirtha Guitelman, Emily Castermans, Catherine Verhaege, Jean-Louis Wémeau, Antoine Tabarin, Carmen Fajardo Montañana, Brigitte Delemer, Veronique Kerlan, Jean-Louis Sadoul, Christine Cortet Rudelli, Françoise Archambeaud, Sabine Zacharieva, Marily Theodoropoulou, Thierry Brue, Alain Enjalbert, Vincent Bours, Natalia S Pellegata, and Albert Beckers

Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15–25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27I119T shows an abnormal migration pattern by SDS–PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

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C R C Pieterman, S M Sadowski, J E Maxwell, M H G Katz, K E Lines, C M Heaphy, A Tirosh, J E Blau, N D Perrier, M A Lewis, J P Metzcar, D M Halperin, R V Thakker, and G D Valk

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27–29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

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Zhigang Zhao and Guohua Zeng

Early prostate cancer antigen (EPCA) has been recently suggested as a novel biomarker in malignant and premalignant lesions of the prostate. This study was to examine serum expression of EPCA and to further clarify the relationship between initial serum EPCA levels and the presence of subsequent cancer in the individuals with isolated high-grade prostatic intraepithelial neoplasia (HGPIN). An indirect ELISA was used for initial serum EPCA measurement in 112 men with isolated HGPIN, who were enrolled and completed a follow-up of ≥5 years. All patients had a detectable concentration of EPCA in the initial serum, with a mean of 0.64±0.13 absorbance at 450 nm. Thirty-three patients had an initial serum EPCA level of ≥1.10, in which 31 cases were subsequently identified as having prostate cancer on follow-up. However, in the remaining 79 cases, serum EPCA levels were all <1.10, and none was diagnosed with cancer later. Statistical analysis showed a significantly higher serum ECPA level in isolated HGPIN patients with subsequent cancer than those without cancer (P<0.001). The area under the receiver operating characteristic curves showed that serum EPCA level had better predictive accuracy of cancer onset on follow-up than prostate specific antigen velocity and abnormal digital rectal examination findings. Furthermore, univariate and multivariate Cox regression analyses demonstrated the predictive performance independently by initial serum EPCA≥1.10 absorbance (relative risk, 3.32; 95% confidence intervals, 2.62–5.03, P<0.001). These preliminary findings first show the potential of serum EPCA to serve as a significant predictor for subsequent cancer in isolated HGPIN.

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S Fontanière, J Tost, A Wierinckx, J Lachuer, J Lu, N Hussein, F Busato, I Gut, Z-Q Wang, and C-X Zhang

Mutations of the MEN1 gene lead to the occurrence of multiple endocrine neoplasia type 1 (MEN1). To gain insights into the mechanisms of the tumorigenesis related to MEN1 inactivation, we have used mice in which the Men1 gene was specifically disrupted in pancreatic β-cells. In these mice, we observed full penetrance of insulinoma with defined histological characteristics of tumorigenesis. To identify the genetic factors taking part in the tumour development, we performed gene expression profiling analysis of these insulinomas at different stages. Here, we show that in late stage insulinomas, 56 genes are up-regulated and 194 are down-regulated more than fourfold compared with normal pancreatic islets. Clustering analysis reveals the deregulation of Hox gene family and the genes involved in cell proliferation and cell cycle control. The altered expression of Igf2, Igfbp3 and Igfbp6 as well as cyclin A2, B2 and D2 are confirmed by quantitative RT-PCR, with the overexpression of all the three cyclins found in early stage insulinomas. Moreover, an increased proportion of cyclin A2- and D2-expressing cells and the overexpression of insulin-like growth factor 2 (IGF2) protein are detected in mouse Men1 insulinomas by immunostaining. Interestingly, the analysis of DNA methylation patterns by quantitative serial pyrosequencing reveals that four specific CpGs in the intragenic differentially methylated region 2 (DMR2) region of the Igf2 gene known to augment transcription through methylation are significantly hypermethylated in insulinomas of Men1 β-cell mutant mice at 6 and 10 months of age, even before IGF2 overexpression can be detected. Thus, our data indicate the involvement of both genetic and epigenetic mechanisms in early tumorigenesis of β-cells related to MEN1 inactivation.

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Y M H Jonkers, S M H Claessen, A Perren, S Schmid, P Komminoth, A A Verhofstad, L J Hofland, R R de Krijger, P J Slootweg, F C S Ramaekers, and E-J M Speel

Endocrine pancreatic tumors (EPTs) comprise a highly heterogeneous group of tumors with different clinical behavior and genetic makeup. Insulinomas represent the predominant syndromic subtype of EPTs. The metastatic potential of insulinomas can frequently not be predicted using histopathological criteria, and also molecular markers indicating malignant progression are unreliable because of the small number of cases per subtype studied so far. For the identification of reliable indicators of metastatic disease, we investigated 62 sporadic insulinomas (44 benign and 18 tumors with metastases) by means of comparative genomic hybridization (CGH). In addition, the role of MEN1 (multiple endocrine neoplasia type 1) gene mutations was determined to assess specific chromosomal alterations associated with dysfunction of this endocrine tumor-related tumor suppressor gene. Only one case with a somatic MEN1 mutation was identified (1527del7bp), indicating that the MEN1 gene plays a minor pathogenic role in sporadic insulinomas. CGH analysis revealed that the total number of aberrations per tumor differs strongly between the benign and the malignant group (4.2 vs 14.1; P<0.0001). Furthermore, chromosome 9q gain was found to be the most frequent aberration in both benign and malignant insulinomas, whereas chromosome 6q losses and 12q, 14q and 17pq gains are strongly associated with metastatic disease. Our study shows that chromosomal instability, as defined by ≥5 gains together with ≥5 losses, or total number of gains and losses ≥8, rather than parameters such as tumor size and proliferation index, is the most powerful indicator for the development of metastatic disease in patients with sporadic insulinoma.