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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

Accession codes

Accessions

Gene Expression Omnibus

Sequence Read Archive

References

  1. 1

    Li, M. et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. 43, 828–829 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Parsons, D.W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Pleasance, E.D. et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184–190 (2010).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Katoh, M. Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol. Ther. 6, 832–839 (2007).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Panani, A.D. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 266, 99–115 (2008).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Huang, W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. Nat. Protoc. 4, 44–57 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  Google Scholar 

  10. 10

    Compton, A.G. et al. Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy. Am. J. Hum. Genet. 83, 714–724 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Su, J.L. et al. Knockdown of contactin-1 expression suppresses invasion and metastasis of lung adenocarcinoma. Cancer Res. 66, 2553–2561 (2006).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Berx, G. & van Roy, F. Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb. Perspect. Biol. 1, a003129 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Wang, Y. Wnt/Planar cell polarity signaling: a new paradigm for cancer. Mol. Cancer Ther. 8, 2103–2109 (2009).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Saburi, S. et al. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat. Genet. 40, 1010–1015 (2008).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Mao, Y. et al. Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development 138, 947–957 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Mahoney, P.A. et al. The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily. Cell 67, 853–868 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Qi, C., Zhu, Y.T., Hu, L. & Zhu, Y.J. Identification of Fat4 as a candidate tumor suppressor gene in breast cancers. Int. J. Cancer 124, 793–798 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Ramensky, V. et al. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Agrawal, N. et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333, 1154–1157 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Deng, N. et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut published online, doi:0.1136/gutjnl-2011-301839 (7 February 2012).

  21. 21

    Van Loo, P. et al. Allele-specific copy number analysis of tumors. Proc. Natl. Acad. Sci. USA 107, 16910–16915 (2010).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Cuadrado, M., Sacristán, M. & Antequera, F. Species-specific organization of CpG island promoters at mammalian homologous genes. EMBO Rep. 2, 586–592 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat. Rev. Cancer 4, 118–132 (2004).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Wiegand, K.C. et al. Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J. Pathol. 224, 328–333 (2011).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Wang, K. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 43, 1219–1223 (2011).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Wiegand, K.C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Van Rechem, C., Boulay, G. & Leprince, D. HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A. Biochem. Biophys. Res. Commun. 385, 586–590 (2009).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Gao, X. et al. ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a. Proc. Natl. Acad. Sci. USA 105, 6656–6661 (2008).

    CAS  Article  Google Scholar 

  31. 31

    Guan, B., Wang, T.L. & Shih, IeM. ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res. 71, 6718–6727 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Neuhaus, E.M. et al. Activation of an olfactory receptor inhibits proliferation of prostate cancer cells. J. Biol. Chem. 284, 16218–16225 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Spicer, Z. et al. Stomachs of mice lacking the gastric H,K-ATPase α-subunit have achlorhydria, abnormal parietal cells, and ciliated metaplasia. J. Biol. Chem. 275, 21555–21565 (2000).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Fuereder, T. et al. Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [18F]FLT uptake. Clin. Cancer Res. 17, 5322–5332 (2011).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  39. 39

    Olshen, A.B. et al. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004).

    Article  Google Scholar 

  40. 40

    Ooi, C.H. et al. Oncogenic pathway combinations predict clinical prognosis in gastric cancer. PLoS Genet. 5, e1000676 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

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.

Corresponding authors

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

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading