skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

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]
+ Show Author Affiliations
  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.
Copy to clipboard
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.
Copy to clipboard
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.
Copy to clipboard
@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}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI:  10.1038/ncomms9683
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 36 works
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families
journal, March 1998

  • Ford, D.; Easton, D. F.; Stratton, M.
  • The American Journal of Human Genetics, Vol. 62, Issue 3
  • DOI: 10.1086/301749

Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2
journal, October 2003

Prevalence and Penetrance of Germline BRCA1 and BRCA2 Mutations in a Population Series of 649 Women with Ovarian Cancer
journal, March 2001

  • Risch, Harvey A.; McLaughlin, John R.; Cole, David E. C.
  • The American Journal of Human Genetics, Vol. 68, Issue 3
  • DOI: 10.1086/318787

Role of BRCA1 and BRCA2 mutations in pancreatic cancer
journal, May 2007

Somatic mutations in the BRCA1 gene in sporadic ovarian tumours
journal, April 1995

  • Merajver, Sofia D.; Pham, Trinh M.; Caduff, Rosemarie F.
  • Nature Genetics, Vol. 9, Issue 4
  • DOI: 10.1038/ng0495-439

Mutation analysis in the BRCA2 gene in primary breast cancers
journal, June 1996

  • Miki, Yoshio; Katagiri, Toyomasa; Kasumi, Fujio
  • Nature Genetics, Vol. 13, Issue 2
  • DOI: 10.1038/ng0696-245

Sensing and repairing DNA double-strand breaks
journal, May 2002

Mutational Processes Molding the Genomes of 21 Breast Cancers
journal, May 2012

Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast Cancer
journal, March 2006

High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs
journal, October 2008

  • Rottenberg, S.; Jaspers, J. E.; Kersbergen, A.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 44
  • DOI: 10.1073/pnas.0806092105

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
journal, April 2005

  • Farmer, Hannah; McCabe, Nuala; Lord, Christopher J.
  • Nature, Vol. 434, Issue 7035
  • DOI: 10.1038/nature03445

Signatures of mutational processes in human cancer
journal, August 2013

  • Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.
  • Nature, Vol. 500, Issue 7463
  • DOI: 10.1038/nature12477

Mutational signatures: the patterns of somatic mutations hidden in cancer genomes
journal, February 2014

  • Alexandrov, Ludmil B.; Stratton, Michael R.
  • Current Opinion in Genetics & Development, Vol. 24
  • DOI: 10.1016/j.gde.2013.11.014

Mechanisms underlying mutational signatures in human cancers
journal, July 2014

  • Helleday, Thomas; Eshtad, Saeed; Nik-Zainal, Serena
  • Nature Reviews Genetics, Vol. 15, Issue 9
  • DOI: 10.1038/nrg3729

Deciphering Signatures of Mutational Processes Operative in Human Cancer
journal, January 2013

Whole genomes redefine the mutational landscape of pancreatic cancer
journal, February 2015

  • Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie
  • Nature, Vol. 518, Issue 7540
  • DOI: 10.1038/nature14169

Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
journal, May 2014

  • Wang, Kai; Yuen, Siu Tsan; Xu, Jiangchun
  • Nature Genetics, Vol. 46, Issue 6
  • DOI: 10.1038/ng.2983

Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes
journal, April 2012

  • Zang, Zhi Jiang; Cutcutache, Ioana; Poon, Song Ling
  • Nature Genetics, Vol. 44, Issue 5
  • DOI: 10.1038/ng.2246

Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer
journal, October 2011

  • Wang, Kai; Kan, Junsuo; Yuen, Siu Tsan
  • Nature Genetics, Vol. 43, Issue 12
  • DOI: 10.1038/ng.982

Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
journal, June 2010

  • Ferlay, Jacques; Shin, Hai-Rim; Bray, Freddie
  • International Journal of Cancer, Vol. 127, Issue 12
  • DOI: 10.1002/ijc.25516

dbSNP: the NCBI database of genetic variation
journal, January 2001

Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants
journal, November 2012

  • Fu, Wenqing; O’Connor, Timothy D.; Jun, Goo
  • Nature, Vol. 493, Issue 7431
  • DOI: 10.1038/nature11690

The UCSC Genome Browser database: extensions and updates 2011
journal, November 2011

  • Dreszer, T. R.; Karolchik, D.; Zweig, A. S.
  • Nucleic Acids Research, Vol. 40, Issue D1
  • DOI: 10.1093/nar/gkr1055

Genome sequencing of normal cells reveals developmental lineages and mutational processes
journal, June 2014

  • Behjati, Sam; Huch, Meritxell; van Boxtel, Ruben
  • Nature, Vol. 513, Issue 7518
  • DOI: 10.1038/nature13448

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma
journal, January 2014

  • Bolli, Niccolo; Avet-Loiseau, Hervé; Wedge, David C.
  • Nature Communications, Vol. 5, Issue 1
  • DOI: 10.1038/ncomms3997

Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer
journal, October 2014

  • Ju, Young Seok; Alexandrov, Ludmil B.; Gerstung, Moritz
  • eLife, Vol. 3
  • DOI: 10.7554/eLife.02935

Transmissible Dog Cancer Genome Reveals the Origin and History of an Ancient Cell Lineage
journal, January 2014

Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer
journal, April 2014

  • Nik-Zainal, Serena; Wedge, David C.; Alexandrov, Ludmil B.
  • Nature Genetics, Vol. 46, Issue 5
  • DOI: 10.1038/ng.2955

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing
journal, February 2014

  • Gerlinger, Marco; Horswell, Stuart; Larkin, James
  • Nature Genetics, Vol. 46, Issue 3
  • DOI: 10.1038/ng.2891
    [ × clear filter / sort ]

    Works referencing / citing this record:

    Mutational signatures associated with tobacco smoking in human cancer
    journal, November 2016

      [ × clear filter / sort ]

      Similar records in OSTI.GOV collections: