A mutational signature in gastric cancer suggests therapeutic strategies

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. 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.

[1]  B. Rosen,et al.  Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. , 2001, American journal of human genetics.

[2]  Asif U. Tamuri,et al.  Genome sequencing of normal cells reveals developmental lineages and mutational processes , 2014, Nature.

[3]  Serena Nik-Zainal,et al.  Mechanisms underlying mutational signatures in human cancers , 2014, Nature Reviews Genetics.

[4]  J Chang-Claude,et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. , 1998, American journal of human genetics.

[5]  T. Walsh,et al.  Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. , 2006, JAMA.

[6]  A. Børresen-Dale,et al.  Mutational Processes Molding the Genomes of 21 Breast Cancers , 2012, Cell.

[7]  J. Kench,et al.  Whole genomes redefine the mutational landscape of pancreatic cancer , 2015, Nature.

[8]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[9]  S. Jackson,et al.  Sensing and repairing DNA double-strand breaks. , 2002, Carcinogenesis.

[10]  M. King,et al.  Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2 , 2003, Science.

[11]  G. Parmigiani,et al.  Heterogeneity of genomic evolution and mutational profiles in multiple myeloma , 2014, Nature Communications.

[12]  Bin Tean Teh,et al.  Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes , 2012, Nature Genetics.

[13]  F. Collins,et al.  Somatic mutations in the BRCA1 gene in sporadic ovarian tumours , 1995, Nature Genetics.

[14]  Herbert Waldmann,et al.  Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA 1 and BRCA 2 , 2015 .

[15]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[16]  David C Whitcomb,et al.  Role of BRCA1 and BRCA2 mutations in pancreatic cancer , 2006, Gut.

[17]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of gastric adenocarcinoma , 2014, Nature.

[18]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2013 , 2012, Nucleic Acids Res..

[19]  M. Stratton,et al.  Deciphering Signatures of Mutational Processes Operative in Human Cancer , 2013, Cell reports.

[20]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[21]  Yusuke Nakamura,et al.  Mutation analysis in the BRCA2 gene in primary breast cancers , 1996, Nature Genetics.

[22]  Adam P Butler,et al.  Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer , 2014, Nature Genetics.

[23]  M. Stratton,et al.  Mutational signatures: the patterns of somatic mutations hidden in cancer genomes , 2014, Current opinion in genetics & development.

[24]  P. A. Futreal,et al.  Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing , 2014, Nature Genetics.

[25]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[26]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[27]  Shibing Deng,et al.  Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer , 2014, Nature Genetics.

[28]  P. Borst,et al.  High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs , 2008, Proceedings of the National Academy of Sciences.

[29]  Zhengyan Kan,et al.  Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer , 2011, Nature Genetics.

[30]  S. Gabriel,et al.  Analysis of 6,515 exomes reveals a recent origin of most human protein-coding variants , 2012, Nature.