Journal
GENOME BIOLOGY
Volume 13, Issue 12, Pages -Publisher
BMC
DOI: 10.1186/gb-2012-13-12-r115
Keywords
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Funding
- Agency for Science Technology and Research (A*STAR), Singapore
- Translational Clinical Research (TCR) Flagship Programme -'The Singapore Gastric Cancer Consortium-Improving Outcomes for Our Patients'
- National Cancer Institute (USA) [NCI: 5 R33 CA126996-02]
- Lee Foundation
- National Cancer Centre Research Foundation
- Genome Institute of Singapore internal research funds from the National Medical Research Council of Singapore
- Biomedical Research Council (BMRC) of A*STAR
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Background: Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability. Results: Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer - against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer. Conclusions: These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.
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