74IN - Towards new molecular classification for neuroendocrine tumours

Date 28 September 2014
Event ESMO 2014
Session Neuroendocrine tumours: The cutting edge and a glimpse into the future
Topics Neuroendocrine Cancers
Pathology/Molecular Biology
Presenter Aldo Scarpa
Citation Annals of Oncology (2014) 25 (suppl_4): iv27-iv28. 10.1093/annonc/mdu307
Authors A. Scarpa
  • Arc-net Centre For Applied Research On Cancer And Department Of Patologia E Diagnostica, Anatomia Patologica, Universita' di Verona, 37134 - Verona/IT

Abstract

Body

Abstract:

A total of 264 pancreatic endocrine tumors (PanNETs) have been studied. A discovery set of 37 cases was subjected to exome sequencing that revealed recurrent mutations in a number of known and previously unidentified genes including ARID1A (2.5%), ATM (5.5%), ATRX (12%), DAXX (20%), MEN1 (35%), MTOR (2.7%), PTEN (8%), TSC2 (5.5%), and TAF1 (3.8%). A prevalence screen was performed on a series of 227 PanNETs from different institutions using targetted next-generation sequencing for these genes using Ion Torrent technology. A series of 90 samples were further analyzed by SNP array to investigate presence of copy number alterations and by immunohistochemistry for Atrx, Daxx, Menin, Pten, and Atm. ATRX, DAXX and PTEN mutations clustered in a group of samples (50%) showing a set of recurrent chromosome losses (RCL). This RCL group showed an increased (+59%) overall mutation rate, correlated with the presence of MEN1 mutations (P < 0.001), presence of distant metastasis (P = 0.001); it was strongly associated with the ALT phenotype (P < 0.001), and showed a significant loss of Pten (P < 0.001) and Daxx (P = 0.001) expression. Expression profiling was available for 72 PanNETs and showed that PanNETs can be classified into three distinctive subtypes: well-differentiated insulinoma-like tumors (IT), metastasis-like primaries (MLP), and an intermediate subtype (INT). This latter subtype revealed as the mutation-enriched subtype. Comparison of mRNA and microRNA transcriptomes of human PanNETs and RIP1-TAG2 engineered mouse model of PanNET showed that the mouse tumors could be classified into two distinctive subtypes, including the IT and MLP subtypes, while lacked the mutation enriched intermediate subtype. MLP subtype also expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting a different cell-of-origin or tumorigenesis pathway. PanNET whole genome sequencing of 90 cases confirmed MEN1 as the master tumour suppressor in this rare tumour subtype with gene inactivation in >60% of patients via somatic mutation (50%), germline mutation (5%), and chromothripsis of 11q13. CNV analysis separated the cohort into three classes that are currently under investigation.

Disclosure:

A. Scarpa: I declare the following potential conflicts of interest: Novartis unrestricted grant for molecular alterations of pancreas endocrine neoplasia.