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Marta Kaczmarek-Ryś, Katarzyna Ziemnicka, Andrzej Pławski, Bartłomiej Budny, Michał Michalak, Szymon Hryhorowicz, Justyna Hoppe-Gołębiewska, Paweł Boruń, Monika Gołąb, Małgorzata Czetwertyńska, Maria Sromek, Marlena Szalata, Marek Ruchała, and Ryszard Słomski

The clinical course of medullary thyroid carcinoma (MTC) associated with the MEN2A syndrome as well as of sporadic MTC shows considerable heterogeneity. The disease picture varies not only between the same RET proto-oncogene mutation carriers but also among sporadic MTC patients with no RET germinal mutations, which suggests the involvement of additional modulators of the disease. However, genetic factors responsible for this heterogeneity of the MTC clinical course still remain unknown. The aim of this study was to determine if polymorphic variants or specific haplotypes of the RET gene may modify the MTC clinical course. We genotyped the following loci: c.73+9277T>C, c.135G>A, c.1296A>G, c.2071G>A, c.2307T>C, c.2508C>T and c.2712C>G in 142 MTC patients and controls. We demonstrated considerable differences in the genotypes distribution within c.73+9277T>C, c.135G>A and c.2307T>C loci. Our results show that the c.73+9277T variant associated with a decreased activity of the MCS+9.7 RET enhancer is rare in hereditary MTC patients with primary hyperparathyroidism, and thus, may influence the MTC clinical picture. The decreased activity of the RET promoter enhancer reduces RET expression level and may counterbalance the activating mutation in this gene. Frequent co-occurrence of the c.73+9277T allele with p.E768D, p.Y791F, p.V804M or p.R844Q RET mutations may be associated with their attenuation and milder clinical picture of the disease. Haplotypes analysis showed that C-G-A-G-T-(C)-C (c.73+9277T>C – c.135G>A – c.1296A>G – c.2071G>A – c.2307T>G – (c.2508C>T) – c.2712C>G) alleles combination predisposes to pheochromocytomas and primary hyperparathyroidism. We consider that RET haplotypes defining may become an auxiliary diagnostic tool in MTC patients.

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P H Kann, E Balakina, D Ivan, D K Bartsch, S Meyer, K-J Klose, Th Behr, and P Langer

Endoscopic ultrasound (EUS) enables detection and localization of pancreatic neuroendocrine tumours. Even small tumours down to a diameter of 1–2 mm can be visualized. Since such small tumours usually cannot be detected by computed tomography (ct), magnetic resonance imaging (mri) and somatostatin receptor scintigraphy (srs), and experience with EUS imaging is limited, there is no clear evidence for clinical management in multiple endocrine neoplasia type 1 (MEN1). Knowledge about the natural course of growth and metastatic distribution is mandatory to come to appropriate clinical decisions and guidelines. This prospective study was aimed to assess the natural course of small (<15 mm) neuroendocrine pancreatic tumours without clinical symptoms due to endocrine activity or mechanical problems and without clear indication for surgical therapy in MEN1 by EUS.

A total of 82 asymptomatic tumours <15 mm (5.9 ± 3.2 mm diameter at baseline) in 20 patients with MEN1-disease (8 female/12 male, 43 ± 13 years) were studied over a period of 20 ± 12 months (33.8 patient years, 106.7 tumour years) by EUS. Change in largest diameter of each tumour and annual tumour incidence rate in the patients’ cohort were calculated.

Increase of largest tumour diameter was found to be 1.3 ± 3.2% per month, annual tumour incidence rate 0.62 new tumours per patient year. In one patient, rapid progressive pancreatic manifestation of MEN1 was observed. There was no evidence in ct and/or srs and/or mri for metastatic disease in all patients. Only 4/84 (4.8%) pancreatic tumours could be visualized by computed tomography, 5/79 (6.3%) by somatostatin receptor imaging and 4/39 (10.3%) by magnetic resonance imaging.

Small asymptomatic neuroendocrine pancreatic tumours in MEN1 usually seem to grow slowly. Annual tumour incidence rate is low. However, faster growing tumours and patients with rapidly progressive disease can be observed. Risk for obvious metastatic disease from asymptomatic neuroendocrine pancreatic tumours <15 mm in MEN1 seems to be low.

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Christodoulos P Pipinikas, Alison M Berner, Teresa Sposito, and Christina Thirlwell

Neuroendocrine neoplasms (NENs) are a relatively rare group of heterogeneous tumours originating from neuroendocrine cells found throughout the body. Pancreatic NENs (PanNENs) are the second most common pancreatic malignancy accounting for 1–3% of all neoplasms developing in the pancreas. Despite having a low background mutation rate, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes (PTEN, TSC1/2) are implicated in disease development and progression. Their increased incidence coupled with advances in sequencing technologies has reignited the interest in PanNEN research and has accelerated the acquisition of molecular data. Studies utilising such technological advances have further enriched our knowledge of PanNENs’ biology through novel findings, including higher-than-expected presence of germline mutations in 17% of sporadic tumours of no familial background, identification of novel mutational signatures and complex chromosomal rearrangements and a dysregulated epigenetic machinery. Integrated genomic studies have progressed the field by identifying the synergistic action between different molecular mechanisms, while holding the promise for deciphering disease heterogeneity. Although our understanding is far from being complete, these novel findings have provided the optimism of shaping the future of PanNEN research, ultimately leading to an era of precision medicine for NETs. Here, we recapitulate the existing knowledge on pancreatic neuroendocrine tumours (PanNETs) and discuss how recent, novel findings have furthered our understanding of these complex tumours.

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Jie Cai, Lin Li, Lei Ye, Xiaohua Jiang, Liyun Shen, Zhibo Gao, Weiyuan Fang, Fengjiao Huang, Tingwei Su, Yulin Zhou, Weiqing Wang, and Guang Ning

Activating rearranged during transfection (RET) mutations function as the initiating causative mutation for multiple endocrine neoplasia type 2A (MEN2A). However, no conclusive findings regarding the non-RET genetic events have been reported. This is the first study, to our knowledge, examining genomic alterations in matched MEN2A-associated tumors. We performed exome sequencing and SNP array analysis of matched MEN2A tumors and germline DNA. Somatic alterations were validated in an independent set of patients using Sanger sequencing. Genes of functional interest were further evaluated. The germline RET mutation was found in all MEN2A-component tumors. Thirty-two somatic mutations were identified in the nine MEN2A-associated tumors, of which 28 (87.5%) were point mutations and 4 (12.5%) were small insertions, duplications, or deletions. We sequenced all the mutations as well as coding sequence regions of the 12 genes in an independent sample set including 35 medullary thyroid cancers (20 MEN2A) and 34 PCCs (22 MEN2A), but found no recurrent mutations. Recurrent alterations were found in 13 genes with either mutations or alterations in copy number, including an EIF4G1 mutation (p. E1147V). Mutation of EIF4G1 led to increased cell proliferation and RET/MAPK phosphorylation, while knockdown of EIF4G1 led to reduced cell proliferation and RET/MAPK phosphorylation in TT, MZ-CRC1, and PC-12 cells. We found fewer somatic mutations in endocrine tumors compared with non-endocrine tumors. RET was the primary driver in MEN2A-associated tumors. However, low-frequency alterations such as EIF4G1 might participate in MEN2A-associated tumorigenesis, possibly by regulating the activity of the RET pathway.

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Martin B Niederle, Monika Hackl, Klaus Kaserer, and Bruno Niederle

As incidence data on gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have so far only been retrospectively obtained and based on inhomogeneous material, we conducted a prospective study in Austria collecting all newly diagnosed GEP-NETs during 1 year. Using the current WHO classification, the tumor, nodes, metastases (TNM) staging and Ki67 grading and the standard diagnostic procedure proposed by the European Neuroendocrine Tumor Society (ENETS), GEP-NETs from 285 patients (male: 148; female: 137) were recorded. The annual incidence rates were 2.51 per 100 000 inhabitants for men, 2.36 per 100 000 for women. The stomach (23%) was the main site, followed by appendix (21%), small intestine (15%) and rectum (14%). Patients with appendiceal tumours were significantly younger than patients with tumours in any other site. About 46.0% were classified as benign, 15.4% as uncertain, 31.9% as well differentiated malignant and 6.7% as poorly differentiated malignant. Patients with benign or uncertain tumours were significantly younger than patients with malignant tumours. Among the malignant tumours of the digestive tract, 1.49% arose from neuroendocrine cells. For malignant gastrointestinal NETs, the incidence was 0.80 per 100 000: 40.9% were ENETS stage I, 23.8% stage II, 11.6% stage III and 23.8% stage IV. The majority (59.7%) were grade 1, 31.2% grade 2 and 9.1% grade 3. NETs of the digestive tract are more common than previously reported; the majority show benign behaviour, are located in the stomach and are well differentiated. G3 tumours are very rare.

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Maria Domenica Castellone and Rosa Marina Melillo

Medullary thyroid carcinomas (MTC) arise from thyroid parafollicular, calcitonin-producing C-cells and can occur either as sporadic or as hereditary diseases in the context of familial syndromes, including multiple endocrine neoplasia 2A (MEN2A), multiple endocrine neoplasia 2B (MEN2B) and familial MTC (FMTC). In a large fraction of sporadic cases, and virtually in all inherited cases of MTC, activating point mutations of the RET proto-oncogene are found. RET encodes for a receptor tyrosine kinase protein endowed with transforming potential on thyroid parafollicular cells. As in other cancer types, microenvironmental factors play a critical role in MTC. Tumor-associated extracellular matrix, stromal cells and immune cells interact and influence the behavior of cancer cells both in a tumor-promoting and in a tumor-suppressing manner. Several studies have shown that, besides the neoplastic transformation of thyroid C-cells, a profound modification of tumor microenvironment has been associated to the RET FMTC/MEN2-associated oncoproteins. They influence the surrounding stroma, activating cancer-associated fibroblasts (CAFs), promoting cancer-associated inflammation and suppressing anti-cancer immune response. These mechanisms might be exploited to develop innovative anti-cancer therapies and novel prognostic tools in the context of familial, RET-associated MTC.

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Lucieli Ceolin, Marta Amaro da Silveira Duval, Antônio Felippe Benini, Carla Vaz Ferreira, and Ana Luiza Maia

Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

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Yeting Du, Monica Ter-Minassian, Lauren Brais, Nichole Brooks, Amanda Waldron, Jennifer A Chan, Xihong Lin, Peter Kraft, David C Christiani, and Matthew H Kulke

The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted.

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Daniela Cordella, Marina Muzza, Luisella Alberti, Paolo Colombo, Pietro Travaglini, Paolo Beck-Peccoz, Laura Fugazzola, and Luca Persani

Activating mutations of the RET proto-oncogene are associated with inherited syndromes, multiple endocrine neoplasia (MEN2A/2B) and with familial and sporadic medullary thyroid cancer (MTC). Single base pair missense mutations in the extracellular Cys-rich domain are responsible for most MEN2A and familial MTC (FMTC) cases. Rarely, somatic deletions and germline duplications have been described in sporadic MTC and in FMTC. We report the detection and functional studies of a deletion/insertion in exon 11 (c.2646delGinsTTCT) associated with FMTC. This in-frame complex rearrangement leads to an Asn to Lys change (Lys666Asn) and to a Ser insertion. The mutation was found in the proband, who was diagnosed with metastatic MTC at 41 years, and in her son, who presented diffuse C-cells hyperplasia at 4 years of age. The mutation displayed a transforming activity stronger than Ret wild type (Ret-WT) at the focus formation assay and functional analyses after transient and stable transfection revealed an increased autophosphorylation, indicating the constitutive activation of the receptor. The transforming activity may be favoured by an increased stabilization of the fully mature form of the mutant receptor. Dimerization assay demonstrated that the activation mechanism of the complex mutation is not mediated by stable dimer formation. Computational analysis predicted nonconservative alterations in the mutant protein consistent with a possible modification of the conformation of the receptor. In conclusion, the first molecular studies on a complex germline RET mutation lying in the juxtamembrane region of the receptor are reported. Functional analyses showed that alterations at this level too can lead to a ligand independent Ret activation.

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Zijie Feng, Jian Ma, and Xianxin Hua

There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis.