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Whole-genome reconstruction and mutational signatures in gastric cancer

Niranjan Nagarajan1*, Denis Bertrand1, Axel M Hillmer2, Zhi Jiang Zang34, Fei Yao25, Pierre-Étienne Jacques1, Audrey SM Teo2, Ioana Cutcutache6, Zhenshui Zhang2, Wah Heng Lee1, Yee Yen Sia2, Song Gao7, Pramila N Ariyaratne1, Andrea Ho2, Xing Yi Woo1, Lavanya Veeravali8, Choon Kiat Ong9, Niantao Deng10, Kartiki V Desai11, Chiea Chuen Khor124, Martin L Hibberd124, Atif Shahab8, Jaideepraj Rao13, Mengchu Wu14, Ming Teh15, Feng Zhu16, Sze Yung Chin15, Brendan Pang1415, Jimmy BY So17, Guillaume Bourque1819, Richie Soong1415, Wing-Kin Sung1, Bin Tean Teh9, Steven Rozen6, Xiaoan Ruan2, Khay Guan Yeoh16, Patrick BO Tan101214* and Yijun Ruan220*

Author affiliations

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

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Citation and License

Genome Biology 2012, 13:R115  doi:10.1186/gb-2012-13-12-r115

Published: 13 December 2012

Abstract

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.