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Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

Abstract

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

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Figure 1: FAT4 somatic mutations and genomic deletions in gastric cancer.
Figure 2: FAT4 siRNA silencing alters the cellular adhesion, migration and invasion of gastric cancer cells.
Figure 3: ARID1A somatic mutations in gastric cancer.

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Acknowledgements

We thank S.T. Tay, K. Ramnarayanan, A. Pandey, Z. Lei, Y. Liu, Y. Suzuki, S. Ramgopal and the Duke–NUS Genome Biology Facility for technical assistance. We also thank AITbiotech for sequencing services. N.D., I.B.T. and W.Y. are recipients of the NUS Graduate School for Integrative Sciences and Engineering Scholarship. This work was supported by funding from the National Medical Research Council (NMRC/ TCR/001/2007 and NMRC/STAR/0006/2009), the Cancer Science Institute of Singapore, the Genome Institute of Singapore, Duke–NUS Graduate Medical School Singapore and The Lee Foundation.

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Contributions

P.T., B.T.T. and S.R. conceived of and designed the study. Z.J.Z. and P.T. directed the study. I.C., J.R.M., N.D., W.Y., Y.W., S.R., D.B. and Z.J.Z. performed the bioinformatics data analysis. S.L.P., S.L.Z., J.T., V.R., H.L.H., A.G., K.H.L., C.K.O., D.H., S.Y.C., C.C.Y.N., M.L., J.W. and D.P. performed experiments, including the sequencing and functional study. I.B.T., W.K. Wan, S.Y.R., J.S., M.S.-T., K.G.Y., W.K. Wong, Y.-J.Z., P.A.F., B.P., Y.R., A.M.H., N.N., B.T.T. and S.R. contributed samples, reagents, data and comments on the manuscript. Z.J.Z. and P.T. analyzed and interpreted data and wrote the manuscript with the assistance and final approval from all authors.

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Correspondence to Steve Rozen, Bin Tean Teh or Patrick Tan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Tables 1, 2, 4–16 and Supplementary Note. (PDF 1658 kb)

Supplementary Table 3

Non-synonymous somatic point mutations affecting exons or splice sites in 15 gastric adenocarcinomas. (XLSX 63 kb)

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Zang, Z., Cutcutache, I., Poon, S. et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 44, 570–574 (2012). https://doi.org/10.1038/ng.2246

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