Endocrine Abstracts

Pancreatic NETs (PanNETs) are characterized by recurrent molecular alterations, including genetic inactivation of MEN1, ATRX/DAXX, and activation of the PI3K/mTOR pathway. The International Cancer Genome Consortium effort on PanNETs 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. Whole-genome sequencing of 102 primary PanNETs and validation on additional 62 cases defined the genomic events that characterize their pathogenesis. The mutational signatures PanNET harbour include a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase involved in base-excision repair. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, are commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling. While calling for further integration of genetic and epigenetic analyses, these data allow reconciling previous findings in a defined frame, and may provide clinical research with markers for patients stratification and to guide targeted therapy decisions.