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Title: A mutational signature in gastric cancer suggests therapeutic strategies

Abstract

Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.

Authors:
ORCiD logo [1];  [2];  [3];  [3];  [4]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
  2. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Addenbrooke's Hospital National Health Service (NHS) Trust, Cambridge (United Kingdom)
  3. The Univ. of Hong Kong, Queen Mary Hospital, Pokfulam (Hong Kong)
  4. Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1236756
Report Number(s):
LA-UR-15-24068
Journal ID: ISSN 2041-1723; ncomms9683
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biological sciences; cancer; genetics; medical research

Citation Formats

Alexandrov, Ludmil B., Nik-Zainal, Serena, Siu, Hoi Cheong, Leung, Suet Yi, and Stratton, Michael R. A mutational signature in gastric cancer suggests therapeutic strategies. United States: N. p., 2015. Web. doi:10.1038/ncomms9683.
Alexandrov, Ludmil B., Nik-Zainal, Serena, Siu, Hoi Cheong, Leung, Suet Yi, & Stratton, Michael R. A mutational signature in gastric cancer suggests therapeutic strategies. United States. doi:10.1038/ncomms9683.
Alexandrov, Ludmil B., Nik-Zainal, Serena, Siu, Hoi Cheong, Leung, Suet Yi, and Stratton, Michael R. Thu . "A mutational signature in gastric cancer suggests therapeutic strategies". United States. doi:10.1038/ncomms9683. https://www.osti.gov/servlets/purl/1236756.
@article{osti_1236756,
title = {A mutational signature in gastric cancer suggests therapeutic strategies},
author = {Alexandrov, Ludmil B. and Nik-Zainal, Serena and Siu, Hoi Cheong and Leung, Suet Yi and Stratton, Michael R.},
abstractNote = {Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.},
doi = {10.1038/ncomms9683},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {2015},
month = {10}
}

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Cited by: 36 works
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