Research
Whole-genome reconstruction and mutational signatures in gastric cancer
- † Equal contributors
1 Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore
2 Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore
3 Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore
4 Cancer and Stem Cell Biology Program, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore 169857, Singapore
5 Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
6 Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore
7 NUS Graduate School of Integrative Sciences and Engineering, Centre for Life Sciences, Singapore 117456, Singapore
8 Research Computing, Genome Institute of Singapore, Singapore 138672, Singapore
9 NCCS-VARI Translational Research Laboratory, National Cancer Centre, Singapore 169610, Singapore
10 Genomic Oncology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore
11 National Institute of Biomedical Genomics, 2nd Floor Netaji Subash Sanatorium, Kalyani 741251 West Bengal, India
12 Infectious Diseases, Genome Institute of Singapore, Singapore 138672, Singapore
13 Department of Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
14 Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
15 Department of Pathology, National University Health System, National University of Singapore, Singapore 119074, Singapore
16 Department of Medicine, National University Health System, National University of Singapore, Singapore 119074, Singapore
17 Department of Surgery, National University Health System, National University of Singapore, Singapore 119074, Singapore
18 Department of Human Genetics, McGill University, Montréal H3A 1B, Canada
19 McGill University and Genome Quebec Innovation Center, Montréal H3A 1A4, Canada
20 Department of Biochemistry, National University of Singapore, Singapore 119074, Singapore
Genome Biology 2012, 13:R115 doi:10.1186/gb-2012-13-12-r115
Published: 13 December 2012Abstract
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.
