Comprehensive molecular characterization of gastric adenocarcinoma
Cancer Genome Atlas Research Network
Abstract
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
Conflict of interest statement
The author declare no competing financial interests.
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References
- Ferlay, J. et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide. IARC CancerBase 11, , accessed on January 15, 2014 (2013)
- Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol., Microbiol. Scand. 1965;64:31–49. doi: 10.1111/apm.1965.64.1.31.
- WHO Classification of Tumours of the Digestive System 4th edn. (International Agency for Research on Cancer, 2010)
- Uemura N, et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 2001;345:784–789. doi: 10.1056/NEJMoa001999.
- Bertuccio P, et al. Recent patterns in gastric cancer: a global overview. International J. Cancer. 2009;125:666–673. doi: 10.1002/ijc.24290.
- Richards FM, et al. Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum. Mol. Genet. 1999;8:607–610. doi: 10.1093/hmg/8.4.607.
- Keller G, et al. Analysis for microsatellite instability and mutations of the DNA mismatch repair gene hMLH1 in familial gastric cancer. International J Cancer. 1996;68:571–576. doi: 10.1002/(SICI)1097-0215(19961127)68:5<571::AID-IJC3>;2-W.
- Toyota M, et al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 1999;59:5438–5442.
- Tan IB, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011;141:476–485. doi: 10.1053/j.gastro.2011.04.042.
- Lei Z, et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology. 2013;145:554–565. doi: 10.1053/j.gastro.2013.05.010.
- Boussioutas A, et al. Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res. 2003;63:2569–2577.
- Wang K, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nature Genet. 2011;43:1219–1223. doi: 10.1038/ng.982.
- Shen R, Olshen AB, Ladanyi M. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis. Bioinformatics. 2009;25:2906–2912. doi: 10.1093/bioinformatics/btp543.
- Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–833. doi: 10.1053/j.gastro.2009.05.001.
- Matsusaka K, et al. Classification of Epstein–Barr virus-positive gastric cancers by definition of DNA methylation epigenotypes. Cancer Res. 2011;71:7187–7197. doi: 10.1158/0008-5472.CAN-11-1349.
- Geddert H, Zur Hausen A, Gabbert HE, Sarbia M. EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1. Anal. Cell. Pathol. 2010;33:143–149. doi: 10.1155/2010/453764.
- Lee J, et al. High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma. PLoS ONE. 2012;7:e38892. doi: 10.1371/journal.pone.0038892.
- Sukawa Y, et al. Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer. World J. Gastroenterology. 2012;18:6577–6586. doi: 10.3748/wjg.v18.i45.6577.
- Strong MJ, et al. Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy. PLoS Pathog. 2013;9:e1003341. doi: 10.1371/journal.ppat.1003341.
- The Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature487, 330–337 (2012)
- Levine Douglas A. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73. doi: 10.1038/nature12113.
- Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–218. doi: 10.1038/nature12213.
- Bernal M, Ruiz-Cabello F, Concha A, Paschen A, Garrido F. Implication of the β2-microglobulin gene in the generation of tumor escape phenotypes. Cancer Immunol. Immunother. 2012;61:1359–1371. doi: 10.1007/s00262-012-1321-6.
- Greulich H, et al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc. Natl Acad. Sci. USA. 2012;109:14476–14481. doi: 10.1073/pnas.1203201109.
- Grossmann V, et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood. 2011;118:6153–6163. doi: 10.1182/blood-2011-07-365320.
- Pugh TJ, et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012;488:106–110. doi: 10.1038/nature11329.
- Dulak AM, et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nature Genet. 2013;45:478–486. doi: 10.1038/ng.2591.
- Ridley AJ, et al. Cell migration: integrating signals from front to back. Science. 2003;302:1704–1709. doi: 10.1126/science.1092053.
- Thumkeo D, Watanabe S, Narumiya S. Physiological roles of Rho and Rho effectors in mammals. Eur. J. Cell Biol. 2013;92:303–315. doi: 10.1016/j.ejcb.2013.09.002.
- Aznar S, et al. Simultaneous tyrosine and serine phosphorylation of STAT3 transcription factor is involved in Rho A GTPase oncogenic transformation. Mol. Biol. Cell. 2001;12:3282–3294. doi: 10.1091/mbc.12.10.3282.
- Yu H, Jove R. The STATs of cancer–new molecular targets come of age. Nature Rev. Cancer. 2004;4:97–105. doi: 10.1038/nrc1275.
- Palomero T, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nature Genet. 2014;46:166–170. doi: 10.1038/ng.2873.
- Sakata-Yanagimoto M, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nature Genet. 2014;46:171–175. doi: 10.1038/ng.2872.
- Doherty GJ, et al. The endocytic protein GRAF1 is directed to cell-matrix adhesion sites and regulates cell spreading. Mol. Biol. Cell. 2011;22:4380–4389. doi: 10.1091/mbc.e10-12-0936.
- Joneson T, White MA, Wigler MH, Bar-Sagi D. Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS. Science. 1996;271:810–812. doi: 10.1126/science.271.5250.810.
- Türeci O, et al. Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals. Gene. 2011;481:83–92. doi: 10.1016/j.gene.2011.04.007.
- Chen BJ, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clinical Cancer Res. 2013;19:3462–3473. doi: 10.1158/1078-0432.CCR-13-0855.
- Green MR, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clinical Cancer Res. 2012;18:1611–1618. doi: 10.1158/1078-0432.CCR-11-1942.
- The Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature487, 330–337 (2012)
- Fuchs CS, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–39. doi: 10.1016/S0140-6736(13)61719-5.
- Schaefer CF, et al. PID: the pathway interaction database. Nucleic Acids Res. 2009;37:D674–D679. doi: 10.1093/nar/gkn653.
Source: PubMed