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Mutational landscape of gastric adenocarcinoma in Chinese: Implications for prognosis and therapy

  1. Xishan Haoa,f,h,2
  1. aDepartment of Epidemiology and Biostatistics,
  2. fDepartment of Pathology, and
  3. hDepartment of Gastrointestinal Surgery, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People’s Republic of China;
  4. bDepartment of Pathology, University of Texas MD Anderson Cancer Center Informatics Center, Houston, TX 77030;
  5. cCenter of Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261;
  6. dBeijing Genomics Institute-Shenzhen, Shenzhen 518083, Guangdong, People’s Republic of China;
  7. eDepartment of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, People's Republic of China;
  8. gDepartment of Oncology Discovery, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
  9. iDivision of Medical Oncology, Mayo Clinic, Rochester, MN 55905;
  10. jMedical Sciences, Amgen Inc., Thousand Oaks, CA 91320;
  11. kLilly China Research and Development Center and
  12. lTranslational Sciences Oncology, Eli Lilly and Company, Indianapolis, IN 46285;
  13. mTranslational Oncology & Personalized Medicine, AbbVie Inc., North Chicago, IL 60064;
  14. nExploratory Clinical & Translational Research, Bristol-Myers Squibb India, Mumbai 400013, India;
  15. rApplied Genomics and Bioinformatics, Bristol-Myers Squibb, Princeton, NJ 08540;
  16. oLudwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093;
  17. pHuman Cancer Genetics Program, Ohio State University, Columbus, OH 43210;
  18. qThe National Foundation for Cancer Research, Bethesda, MD 20814;
  19. sAsian Fund for Cancer Research, Hong Kong, People's Republic of China; and
  20. tDepartment of Biology, University of Copenhagen, DK-1165 Copenhagen, Denmark

  1. Contributed by Webster K. Cavenee, December 15, 2014 (sent for review November 20, 2014)

Significance

We have identified a lethal subtype of gastric cancer (GC) that is characterized by high levels of clonal heterogeneity and TP53 (tumor protein P53) mutation. We have also uncovered key novel mutations in the targetable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair and identified BRCA2 (breast cancer 2, early onset) mutations as new genetic markers to predict better survival for GC. Our study represents a novel approach for GC personalized medicine and identified novel clinical actionable therapies for GC therapy.

Abstract

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Footnotes

  • ↵1K.C., D.Y., and X. Li contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: wcavenee{at}ucsd.edu, xishanhao{at}sina.com, or wzhang{at}mdanderson.org.

  • Author contributions: K.C., B.S., W.C., D.J.B., J.B., S.D.P., X.Y., C.R., A.B., D.J., P.S.M., C.M.C., Y.M.W., S.K., Y.P., H.C., S.B., W.K.C., W.Z., and X.H. designed research; Z.G., H. Liang, M.L., X. Lu, and L.L. performed research; D.Y., Haixin Li, Y.Z., H.Z., Hui Li, X. Lu, and W.Z. analyzed data; and K.C., D.Y., X. Li, F.S., W.C., X. Lu, W.K.C., and W.Z. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: The sequence reported in this paper has been deposited in the European Genome-phenome Archive database, www.ebi.ac.uk (accession no. EGAS00001001056).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1422640112/-/DCSupplemental.

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