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The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

Venizelos, Andreas ; Elvebakken, Hege ; Perren, Aurel ; Nikolaienko, Oleksii ; Deng, Wei ; Lothe, Inger Marie B ; Couvelard, Anne ; Hjortland, Geir Olav ; Sundlöv, Anna LU orcid and Svensson, Johanna B , et al. (2022) In Endocrine-Related Cancer 29(1). p.1-14
Abstract

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 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... (More)

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 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%). 8/152 (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 indicates a high potential for better personalized treatments.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Endocrine-Related Cancer
volume
29
issue
1
pages
1 - 14
publisher
Society for Endocrinology
external identifiers
  • pmid:34647903
  • scopus:85120829650
ISSN
1479-6821
DOI
10.1530/ERC-21-0152
language
English
LU publication?
yes
id
d942257a-b40a-451a-b3c2-22543e39025e
date added to LUP
2021-10-29 18:38:16
date last changed
2024-04-20 14:26:17
@article{d942257a-b40a-451a-b3c2-22543e39025e,
  abstract     = {{<p>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 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%). 8/152 (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 indicates a high potential for better personalized treatments.</p>}},
  author       = {{Venizelos, Andreas and Elvebakken, Hege and Perren, Aurel and Nikolaienko, Oleksii and Deng, Wei and Lothe, Inger Marie B and Couvelard, Anne and Hjortland, Geir Olav and Sundlöv, Anna and Svensson, Johanna B and Garresori, Harrish and Kersten, Christian and Hofsli, Eva and Detlefsen, Sonke and Krogh, Merete and Sorbye, Halfdan and Knappskog, Stian}},
  issn         = {{1479-6821}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{1--14}},
  publisher    = {{Society for Endocrinology}},
  series       = {{Endocrine-Related Cancer}},
  title        = {{The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms}},
  url          = {{http://dx.doi.org/10.1530/ERC-21-0152}},
  doi          = {{10.1530/ERC-21-0152}},
  volume       = {{29}},
  year         = {{2022}},
}