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.
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.|Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.|Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
Ludmil B
http://orcid.org/0000-0003-3596-4515
LB
Alexandrov
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.|Department of Medical Genetics, Addenbrooke's Hospital National Health Service (NHS) Trust, Cambridge CB2 0QQ, UK.
Serena
S
Nik-Zainal
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Hoi Cheong
HC
Siu
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Suet Yi
SY
Leung
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
Michael R
MR
Stratton
D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D053960:DNA Breaks; D004260:DNA Repair; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*
D019313:BRCA1 Protein; D024682:BRCA2 Protein