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Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer

Nature Genetics volume 43, pages 1219–1223 (2011)Cite this article

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Abstract

Gastric cancer is a heterogeneous disease with multiple environmental etiologies and alternative pathways of carcinogenesis1,2. Beyond mutations in TP53, alterations in other genes or pathways account for only small subsets of the disease. We performed exome sequencing of 22 gastric cancer samples and identified previously unreported mutated genes and pathway alterations; in particular, we found genes involved in chromatin modification to be commonly mutated. A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS). The mutation spectrum for ARID1A differs between molecular subtypes of gastric cancer, and mutation prevalence is negatively associated with mutations in TP53. Clinically, ARID1A alterations were associated with better prognosis in a stage-independent manner. These results reveal the genomic landscape, and highlight the importance of chromatin remodeling, in the molecular taxonomy of gastric cancer.

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Figure 1: Relationship of ARID1A alterations (mutation or protein deficiency) with molecular subtypes of gastric cancer.
Figure 2: Difference in the mutation spectrum of ARID1A between molecular subtypes of gastric cancer.

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Acknowledgements

We thank L. Ng and M.K. Ng for technical assistance and clinicians in the Hong Kong Hospital Authority for clinical care. We thank Illumina for performing whole-exome sequencing.

Author information

Author notes

  1. Neil W Gibson

    Present address: Present address: Regulus Therapeutics, San Diego, California, USA.,

  2. Kai Wang and Junsuo Kan: These authors contributed equally to this work.

Authors and Affiliations

  1. Oncology Research Unit, Pfizer Worldwide Research and Development, La Jolla, California, USA

    Kai Wang, Zhengyan Kan, Paul A Rejto, Neil W Gibson, David J Pocalyko, Mao Mao & Jiangchun Xu

  2. Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

    Junsuo Kan, Siu Tsan Yuen, Tsun Leung Chan, Annie S Y Chan, Wai Yin Tsui, Siu Po Lee, Siu Lun Ho, Anthony K W Chan, Grace H W Cheng & Suet Yi Leung

  3. External Research Solutions, Pfizer Worldwide Research and Development, La Jolla, California, USA

    Stephanie T Shi

  4. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

    Kent Man Chu & Simon Law

  5. Research Embedded Business Technology, Pfizer Worldwide Research and Development, La Jolla, California, USA

    Peter C Roberts

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Contributions

D.J.P., P.A.R., N.W.G., M.M., J.X., S.T.Y. and S.Y.L. conceived of the study. S.T.Y., S.Y.L., J.X. and M.M. directed the study. K.W., S.T.S., P.A.R., J.X., M.M., S.T.Y. and S.Y.L. contributed to the project design. K.W., Z.K. and G.H.W.C. performed the bioinformatics data analysis. J.K., T.L.C., A.S.Y.C., W.Y.T., S.P.L., S.L.H. and A.K.W.C. performed experiments on ARID1A mutation and other molecular analysis. K.M.C. and S.L. contributed samples, data and comments on the manuscript. P.C.R. contributed to data management. K.W., J.K., S.T.Y., M.M., J.X. and S.Y.L. analyzed and interpreted data and wrote the manuscript with the assistance and final approval from all authors.

Corresponding authors

Correspondence to Jiangchun Xu or Suet Yi Leung.

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Competing interests

K.W., S.T.S., Z.K., P.C.R., P.A.R., N.W.G., D.J.P., M.M. and J.X. are employees of Pfizer Inc.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 1–3, 5, 8, 11, 12 and 14–17 and Supplementary Note (PDF 2601 kb)

Supplementary Table 4

List of all somatic mutations identified in the SureSelect All Exon kit baited regions in 22 gastric cancers (XLSX 604 kb)

Supplementary Table 6

Comparison of list of gastric cancer genes with protein altering mutations detected in exome study versus kinome study (XLSX 157 kb)

Supplementary Table 7

List of genes with protein-altering somatic mutations in at least two patients in the gastric cancer cohort and their driver gene scores (XLSX 59 kb)

Supplementary Table 9

Pathways enriched in somatically mutated genes in gastric cancer (XLSX 36 kb)

Supplementary Table 10

List of all protein-altering somatic mutations involving chromatin modification genes in 22 gastric cancers (XLSX 30 kb)

Supplementary Table 13

Complete list of ARID1A and TP53 somatic mutations in 109 gastric cancers and their associated molecular parameters (XLSX 40 kb)

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Wang, K., Kan, J., Yuen, S. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet 43, 1219–1223 (2011). https://doi.org/10.1038/ng.982

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