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Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

Nature Genetics volume 46, pages 573–582 (2014)Cite this article

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Abstract

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.

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Figure 1: Summary of genetic and epigenetic alterations in 100 gastric cancers separated into different histological and molecular subtypes.
Figure 2: Representative Circos plots of the different molecular subtypes of gastric cancer with specific genetic and epigenetic perturbations.
Figure 3: OncoPlot summary of significantly mutated, amplified or deleted genes and representative hypermethylated genes in 100 gastric cancer samples separated into various molecular subtypes.
Figure 4: Summary of protein-altering somatic alterations of MUC6 in gastric cancers.
Figure 5: Distribution of protein alterations encoded in other new top significantly mutated gastric cancer driver genes.
Figure 6: Summary of the RHOA somatic alteration spectrum in gastric cancers.
Figure 7: Functional characterization of RHOA hotspot mutants.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Zang, Z.J. et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat. Genet. 44, 570–574 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pleasance, E.D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Hodis, E. et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  7. Church, D.N. et al. DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer. Hum. Mol. Genet. 22, 2820–2828 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kandoth, C. et al. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dulak, A.M. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat. Genet. 45, 478–486 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nagarajan, N. et al. Whole-genome reconstruction and mutational signatures in gastric cancer. Genome Biol. 13, R115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Youn, A. & Simon, R. Identifying cancer driver genes in tumor genome sequencing studies. Bioinformatics 27, 175–181 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Garcia, E., Carvalho, F., Amorim, A. & David, L. MUC6 gene polymorphism in healthy individuals and in gastric cancer patients from northern Portugal. Cancer Epidemiol. Biomarkers Prev. 6, 1071–1074 (1997).

    CAS  PubMed  Google Scholar 

  14. Kwon, J.A. et al. Short rare MUC6 minisatellites-5 alleles influence susceptibility to gastric carcinoma by regulating gene. Hum. Mutat. 31, 942–949 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Zheng, H. et al. MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays. J. Cancer Res. Clin. Oncol. 132, 817–823 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Koo, B.K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Sehgal, R.N., Gumbiner, B.M. & Reichardt, L.F. Antagonism of cell adhesion by an α-catenin mutant, and of the Wnt-signaling pathway by α-catenin in Xenopus embryos. J. Cell Biol. 139, 1033–1046 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bogaerts, S., Vanlandschoot, A., van Hengel, J. & van Roy, F. Nuclear translocation of αN-catenin by the novel zinc finger transcriptional repressor ZASC1. Exp. Cell Res. 311, 1–13 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Majewski, I.J. et al. An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J. Pathol. 229, 621–629 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. van den Brink, G.R. et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology 121, 317–328 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Ramalho-Santos, M., Melton, D.A. & McMahon, A.P. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127, 2763–2772 (2000).

    CAS  PubMed  Google Scholar 

  22. Blank, M.C. et al. Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis. Development 138, 1207–1216 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Park, S.H., Kim, Y.S., Park, B.K., Hougaard, S. & Kim, S.J. Sequence-specific enhancer binding protein is responsible for the differential expression of ERT/ESX/ELF-3/ESE-1/jen gene in human gastric cancer cell lines: implication for the loss of TGF-β type II receptor expression. Oncogene 20, 1235–1245 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Nakanishi, Y. et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat. Genet. 45, 98–103 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Ahuja, N. et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res. 57, 3370–3374 (1997).

    CAS  PubMed  Google Scholar 

  26. Kang, G.H. et al. CpG island methylation in premalignant stages of gastric carcinoma. Cancer Res. 61, 2847–2851 (2001).

    CAS  PubMed  Google Scholar 

  27. Oue, N. et al. Reduced expression of the TSP1 gene and its association with promoter hypermethylation in gastric carcinoma. Oncology 64, 423–429 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Dvorsky, R., Blumenstein, L., Vetter, I.R. & Ahmadian, M.R. Structural insights into the interaction of ROCKI with the switch regions of RhoA. J. Biol. Chem. 279, 7098–7104 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Maesaki, R. et al. The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1. Mol. Cell 4, 793–803 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Sahai, E., Alberts, A.S. & Treisman, R. RhoA effector mutants reveal distinct effector pathways for cytoskeletal reorganization, SRF activation and transformation. EMBO J. 17, 1350–1361 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bae, C.D., Min, D.S., Fleming, I.N. & Exton, J.H. Determination of interaction sites on the small G protein RhoA for phospholipase D. J. Biol. Chem. 273, 11596–11604 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Chen, X. et al. Variation in gene expression patterns in human gastric cancers. Mol. Biol. Cell 14, 3208–3215 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Watanabe, K. et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat. Biotechnol. 25, 681–686 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. 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 61, 673–684 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Kimura, Y. et al. Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progression. Mod. Pathol. 17, 1328–1337 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Mermel, C.H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tuncel, H. et al. PARP6, a mono(ADP-ribosyl) transferase and a negative regulator of cell proliferation, is involved in colorectal cancer development. Int. J. Oncol. 41, 2079–2086 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Pang, J.C. et al. KIAA0495/PDAM is frequently downregulated in oligodendroglial tumors and its knockdown by siRNA induces cisplatin resistance in glioma cells. Brain Pathol. 20, 1021–1032 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fujii, Y. et al. CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5. Proc. Natl. Acad. Sci. USA 109, 20584–20589 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mutoh, H. et al. Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice. Gut 53, 1416–1423 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rau, T.T. et al. Methylation-dependent activation of CDX1 through NF-κB: a link from inflammation to intestinal metaplasia in the human stomach. Am. J. Pathol. 181, 487–498 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kwon, O.H. et al. Aberrant upregulation of ASCL2 by promoter demethylation promotes the growth and resistance to 5-fluorouracil of gastric cancer cells. Cancer Sci. 104, 391–397 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. van der Flier, L.G. et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, J. et al. Cadherin-17 induces tumorigenesis and lymphatic metastasis in gastric cancer through activation of NFκB signaling pathway. Cancer Biol. Ther. 14, 262–270 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nagl, N.G. Jr., Zweitzig, D.R., Thimmapaya, B., Beck, G.R. Jr. & Moran, E. The c-myc gene is a direct target of mammalian SWI/SNF-related complexes during differentiation-associated cell cycle arrest. Cancer Res. 66, 1289–1293 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Guan, B., Wang, T.L. & Shih Ie, M. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Matsusaka, K. et al. Classification of Epstein-Barr virus–positive gastric cancers by definition of DNA methylation epigenotypes. Cancer Res. 71, 7187–7197 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Zouridis, H. et al. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci. Transl. Med. 4, 156ra140 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Matsuzaki, K. et al. The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer. Clin. Cancer Res. 11, 8564–8569 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Wilson, A.S., Power, B.E. & Molloy, P.L. DNA hypomethylation and human diseases. Biochim. Biophys. Acta 1775, 138–162 (2007).

    CAS  PubMed  Google Scholar 

  53. Sahai, E. & Marshall, C.J. RHO-GTPases and cancer. Nat. Rev. Cancer 2, 133–142 (2002).

    Article  PubMed  Google Scholar 

  54. Braga, V.M., Machesky, L.M., Hall, A. & Hotchin, N.A. The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J. Cell Biol. 137, 1421–1431 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Coleman, M.L. & Olson, M.F. Rho GTPase signalling pathways in the morphological changes associated with apoptosis. Cell Death Differ. 9, 493–504 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Coleman, M.L. et al. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat. Cell Biol. 3, 339–345 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Cox, E.A., Sastry, S.K. & Huttenlocher, A. Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases. Mol. Biol. Cell 12, 265–277 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sahai, E. & Marshall, C.J. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat. Cell Biol. 5, 711–719 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Yoshioka, K., Nakamori, S. & Itoh, K. Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. Cancer Res. 59, 2004–2010 (1999).

    CAS  PubMed  Google Scholar 

  60. Sahai, E., Garcia-Medina, R., Pouyssegur, J. & Vial, E. Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility. J. Cell Biol. 176, 35–42 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Matsuoka, T. et al. RhoA/ROCK signaling mediates plasticity of scirrhous gastric carcinoma motility. Clin. Exp. Metastasis 28, 627–636 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Sakata-Yanagimoto, M. et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 171–175 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Palomero, T. et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat. Genet. 46, 166–170 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yoo, H.Y. et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 371–375 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Saunders, C.T. et al. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28, 1811–1817 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Koo, B.K. et al. Controlled gene expression in primary Lgr5 organoid cultures. Nat. Methods 9, 81–83 (2012).

    Article  CAS  Google Scholar 

  68. Wang, J. et al. CREST maps somatic structural variation in cancer genomes with base-pair resolution. Nat. Methods 8, 652–654 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Staaf, J. et al. Normalization of Illumina Infinium whole-genome SNP data improves copy number estimates and allelic intensity ratios. BMC Bioinformatics 9, 409 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, K. et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17, 1665–1674 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Olshen, A.B., Venkatraman, E.S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004).

    Article  PubMed  Google Scholar 

  72. Yau, C. et al. A statistical approach for detecting genomic aberrations in heterogeneous tumor samples from single nucleotide polymorphism genotyping data. Genome Biol. 11, R92 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang, K. et al. Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma. Hepatology 58, 706–717 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Hu, J. Cancer outlier detection based on likelihood ratio test. Bioinformatics 24, 2193–2199 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kanehisa, M., Goto, S., Sato, Y., Furumichi, M. & Tanabe, M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 40, D109–D114 (2012).

    CAS  PubMed  Google Scholar 

  76. Storey, J.D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank J. Shen for assistance with bioinformatics and clinicians at the Hong Kong Hospital Authority for clinical care. We thank Illumina for performing whole-genome sequencing, TruSeq and array experiments and the Centre for Genomics Sciences at the University of Hong Kong for other sequencing services. Funding for the whole-genome sequencing study and associated validation was provided by Pfizer. Funding for the methylation analysis was provided by the Research Grants Council of the Hong Kong Special Administrative Region (General Research Fund grant HKU7719/10M). Funding for the functional assays was provided by a donation from S.T. Pan.

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Author notes

  1. Jiangchun Xu & Mao Mao

    Present address: Present addresses: Quanticel Pharmaceuticals, San Diego, California, USA (J.X.), and WuXi AppTec, Shanghai, China (M.M.).,

  2. Kai Wang, Siu Tsan Yuen, Jiangchun Xu, Siu Po Lee and Helen H N Yan: These authors contributed equally to this work.

Authors and Affiliations

  1. Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA

    Kai Wang, Jiangchun Xu, Shibing Deng, Tao Xie, Julio Fernandez, Paul A Rejto & Mao Mao

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

    Siu Tsan Yuen, Siu Po Lee, Helen H N Yan, Hoi Cheong Siu, Kok Hoe Chan, Annie S Y Chan, Wai Yin Tsui, Siu Lun Ho, Anthony K W Chan, Jonathan L K Man, Man Kin Ng, April S Chan, Grace H W Cheng & Suet Yi Leung

  3. External Research Solutions, Pfizer Worldwide Research and Development, San Diego, 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. Division of Stem Cell Biology and Developmental Genetics, Medical Research Council (MRC) National Institute for Medical Research, London, UK

    Valentina Foglizzo & Vivian S W Li

  6. Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong

    Yick Pang Ching

  7. Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands

    Hans Clevers

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Contributions

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

Corresponding authors

Correspondence to Mao Mao or Suet Yi Leung.

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Competing interests

K.W., J.X., S.T.S., S.D., T.X., J.F., P.A.R. and M.M. are or were employed by Pfizer, Inc.

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Wang, K., Yuen, S., Xu, J. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 46, 573–582 (2014). https://doi.org/10.1038/ng.2983

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