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Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms

Venizelos, Andreas ; Sorbye, Halfdan ; Elvebakken, Hege ; Perren, Aurel ; Lothe, Inger Marie B. ; Couvelard, Anne ; Hjortland, Geir Olav ; Sundlöv, Anna LU orcid ; Svensson, Johanna and Garresori, Harrish , et al. (2023) In Endocrine-Related Cancer 30(10).
Abstract

High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may... (More)

High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
etiology, germline, HG-GEP NEN, pathogenic variants
in
Endocrine-Related Cancer
volume
30
issue
10
article number
e230057
publisher
Society for Endocrinology
external identifiers
  • pmid:37410378
  • scopus:85168779347
ISSN
1479-6821
DOI
10.1530/ERC-23-0057
language
English
LU publication?
yes
id
1c225731-2bb3-40e8-a1b5-9826c9469b43
date added to LUP
2023-09-20 10:41:53
date last changed
2024-04-19 01:28:02
@article{1c225731-2bb3-40e8-a1b5-9826c9469b43,
  abstract     = {{<p>High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still &lt;10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.</p>}},
  author       = {{Venizelos, Andreas and Sorbye, Halfdan and Elvebakken, Hege and Perren, Aurel and Lothe, Inger Marie B. and Couvelard, Anne and Hjortland, Geir Olav and Sundlöv, Anna and Svensson, Johanna and Garresori, Harrish and Kersten, Christian and Hofsli, Eva and Detlefsen, Sönke and Vestermark, Lene W. and Ladekarl, Morten and Tabaksblat, Elizaveta Mitkina and Knappskog, Stian}},
  issn         = {{1479-6821}},
  keywords     = {{etiology; germline; HG-GEP NEN; pathogenic variants}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  publisher    = {{Society for Endocrinology}},
  series       = {{Endocrine-Related Cancer}},
  title        = {{Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms}},
  url          = {{http://dx.doi.org/10.1530/ERC-23-0057}},
  doi          = {{10.1530/ERC-23-0057}},
  volume       = {{30}},
  year         = {{2023}},
}