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. 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.
Highlights
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
While defective double-strand break repair increases the mutational burden of a cell, increasing the chances of acquiring somatic mutations that lead to neoplastic transformation, it renders a cell more susceptible to cell cycle arrest and subsequent apoptosis when it is exposed to agents such as platinum-based antineoplastic drugs[10,11]
This susceptibility has been successfully leveraged for the development of targeted and less-toxic therapeutic strategies for treatment of breast, ovarian and pancreatic cancers harbouring BRCA1 and/or BRCA2 mutations, notably poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors[10,11]
Summary
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. We used a substantially elaborated version of our previously developed framework for deciphering mutational signatures (Methods) and analysed 7,329,860 somatic mutations from 10,250 pairs of cancer-normal samples derived from 36 distinct types of human cancer, including 607 whole-genome sequences and 9,643 whole-exome sequences (Supplementary Data 1).
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