Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium

Abstract

Neuroendocrine tumours (NETs) may arise throughout the body and are a highly heterogeneous, relatively rare class of neoplasms difficult to study also for the lack of disease models. Despite this, knowledge on their molecular alterations has expanded in the latest years, also building from genetic syndromes causing their onset. Pancreatic NETs (PanNETs) have been among the most studied, and research so far has outlined a series of recurring features, as inactivation of MEN1, VHL, TSC1/2 genes and hyperactivation of the PI3K/mTOR pathway. Next-generation sequencing has added new information by showing the key role of alternative lengthening of telomeres, driven in a fraction of PanNETs by inactivation of ATRX/DAXX. Despite this accumulation of knowledge, single studies often relied on few cases or were limited to the DNA, RNA, protein or epigenetic level with lack of integrative analysis. The International Cancer Genome Consortium aimed at removing these barriers through a strict process of data and samples collection, to produce whole-genome integrated analyses for many tumour types. The results of this effort on PanNETs have been recently published and, while confirming previous observations provide a first snapshot of how heterogeneous is the combination of genetic alterations that drive this tumour type, yet converging into four pathways whose alteration has been enriched by newly discovered mechanisms. While calling for further integration of genetic and epigenetic analyses, these data allow to reconcile previous findings in a defined frame and may provide clinical research with markers for patients stratification and to guide targeted therapy decisions.

Primary renal well‐differentiated neuroendocrine tumour (carcinoid): next‐generation sequencing study of 11 cases

“…Furthermore, recurring features have been reported, such as inactivation of MEN1, VHL, and TSC1/2, hyperactivation of the PI3K-mTOR pathway and inactivation of ATRX/DAXX in a proportion of Pan-NET cases. 67,68 Another group of NETs studied with molecular-genetic techniques were lung carcinoids (typical carcinoid and atypical carcinoid), which often have alterations in the chromatin-remodelling genes MEN1, PSIP1, and ARID1A. 69 On the other hand, lung neuroendocrine carcinomas frequently have inactivating mutations in TP53 and RB1, amplification of MYC family members, and genetic alterations in the PI3K-AKT-mTOR signalling pathway.…”

The Altered Metabolic Molecular Signatures Contribute to the RAD001 Resistance in Gastric Neuroendocrine Tumor

“…As a key regulator for translational control, mTOR integrates various environmental cues to regulate host homeostasis (32). A growing body of evidence shows the link between activated mTOR signaling and tumor formation, including neuroendocrine tumors (33,34). Mutations in genes of mTOR pathway were reported in 14% of pancreatic neuroendocrine tumors (p-NETs) (24).…”

Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers

“…Several publications have also shown chromosome losses affecting genes related to DNA repair or damage checkpoints (VHL, MEN1, ATM, PTEN) in PNENs (Capurso et al 2012, Scarpa et al 2017. In this sense, most recent reviews describe genetic alterations that are consistently related with the loss of MEN1 function, the activation of the PI3K/mTOR pathway, changes in chromatin remodeling and telomeres alteration (Mafficini & Scarpa 2018).…”