Endocrine Abstracts

The genetic landscape of neuroendocrine tumors (NETs) is being rapidly uncovered. It has long been known that, like other endocrine tumors, NETs might occur in the context of familial predisposition syndromes, involving genes like MEN1, VHL, TSC1/TSC2, NF1 and CDKN1B. Recently, several seminal papers have described the main molecular abnormalities underlying sporadic or apparently sporadic NETs. The results confirm that: (a) well differentiated NETs from various sites are genetically distinct; (b) well differentiated and poorly differentiated neuroendocrine neoplasms are genetically distinct and likely correspond to different entities. Pancreatic and lung well differentiated NETs are mainly associated with abnormalities in genes encoding proteins involved in chromatin regulation and telomere control (such as MEN1, DAXX and ATRX in pancreatic NETs, MEN1 again and a number of genes of the SWI/SNF pathway in lung NETs); in addition, recent results have revealed the occurence of fusion transcripts involving EWSR in pancreatic NETs, uncovering a new perspective in the molecular mechanisms underlying pancreatic and perhaps other NETs. In contrast, in well differentiated small intestinal NETs, the molecular landscape appears to be heterogeneous, with a high frequency of chromosomal changes and a wide spectrum of mutations involving various signalling pathways (mTOR, SMAD). Taken together, these results suggest that in well differentiated NETs, several oncogenic mechanisms might be involved: epigenetic dysregulations due to chromosomal and genomic instability, alterations in intracellular signalling pathways, and production of oncogenic proteins. As regards the neoplasms morphologically classified as poorly differentiated neuroendocrine carcinomas, concurrent results show that they might be associated with three different molecular signatures: (a) typical ‘high grade neuroendocrine’ signatures, characterized by mutations in TP53 and Rb, and corresponding to ‘true’ neuroendocrine carcinomas; (b) ‘adenocarcinoma-like’ signatures, corresponding to aggressive carcinomas maskerading as neuroendocrine neoplasms, (c) ‘well differentiated NET’ signatures, corresponding to highly proliferative well differentiated neuroendocrine neoplasms with an aggressive behavior. The molecular tools now available will clearly help to refine the classification of aggressive, high grade neuroendocrine malignancies, but their clinical and therapeutic impact remains to be evaluated. As for low grade neuroendocrine malignancies, the main interest of molecular profiling will probably be prognostic and predictive.