The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated fro...

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Published in:Endocrine-related cancer Vol. 29; no. 1; p. 1
Main Authors: Venizelos, Andreas, Elvebakken, Hege, Perren, Aurel, Nikolaienko, Oleksii, Deng, Wei, Lothe, Inger Marie B, Couvelard, Anne, Hjortland, Geir Olav, Sundlöv, Anna, Svensson, Johanna, Garresori, Harrish, Kersten, Christian, Hofsli, Eva, Detlefsen, Sönke, Krogh, Merete, Sorbye, Halfdan, Knappskog, Stian
Format: Journal Article
Language:English
Published: England 01.01.2022
Subjects:
Carcinoma, Neuroendocrine - genetics
Humans
Intestinal Neoplasms - genetics
Intestinal Neoplasms - pathology
Neuroendocrine Tumors - genetics
Neuroendocrine Tumors - pathology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Proto-Oncogene Proteins B-raf
Retinoblastoma-Binding Protein 2
Stomach Neoplasms - genetics
Stomach Neoplasms - pathology
neuroendocrine carcinoma
neuroendocrine neoplasms
genetic alterations
molecular markers
gastroenteropancreatic
high-grade
ISSN:1479-6821, 1479-6821
Online Access:Get more information
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Summary:High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.
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ISSN:1479-6821
1479-6821
DOI:10.1530/ERC-21-0152