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27-03-2015 | Gastric cancer | Article

Molecular Classification of Gastric Adenocarcinoma: Translating New Insights from The Cancer Genome Atlas Research Network

Journal: Current Treatment Options in Oncology

Authors: Yu Sunakawa, MD, PhD, Heinz-Josef Lenz, MD

Publisher: Springer US

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Abstract

Gastric cancer is a heterogenous cancer, which may be classified into several distinct subtypes based on pathology and epidemiology, each with different initiating pathological processes and each possibly having different tumor biology. A classification of gastric cancer should be important to select patients who can benefit from the targeted therapies or to precisely predict prognosis. The Cancer Genome Atlas (TCGA) study collaborated with previous reports regarding subtyping gastric cancer but also proposed a refined classification based on molecular characteristics. The addition of the new molecular classification strategy to a current classical subtyping may be a promising option, particularly stratification by Epstein–Barr virus (EBV) and microsatellite instability (MSI) statuses. According to TCGA study, EBV gastric cancer patients may benefit the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies or phosphoinositide 3-kinase (PI3K) inhibitors which are now being developed. The discoveries of predictive biomarkers should improve patient care and individualized medicine in the management since the targeted therapies may have the potential to change the landscape of gastric cancer treatment, moreover leading to both better understanding of the heterogeneity and better outcomes. Patient enrichment by predictive biomarkers for new treatment strategies will be critical to improve clinical outcomes. Additionally, liquid biopsies will be able to enable us to monitor in real-time molecular escape mechanism, resulting in better treatment strategies.
Literature
1.
Hohenberger P, Gretschel S. Gastric cancer. Lancet. 2003;362:305–15.PubMedCrossRef
2.
Shah MA, Kelsen DP. Gastric cancer: a primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Canc Netw. 2010;8:437–47.PubMed
3.••
Shah MA et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res. 2011;17:2693–701. Most important classification of gastric cancer among previous reports.PubMedCentralPubMedCrossRef
4.
Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354–62.PubMedCentralPubMed
5.
Tan IB, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 2011;141:476–85, 485 e1-11.
6.
Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.PubMed
7.
Parsonnet J et al. Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst. 1991;83:640–3.PubMedCrossRef
8.
Galon J et al. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol. 2014;232:199–209.PubMedCentralPubMedCrossRef
9.••
Wang K et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46:573–82. Important research of molecular profiing using whole-genome sequence in gastric cancer.PubMedCrossRef
10.•
Liu Z et al. Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis. Clin Cancer Res. 2014;20:4598–612. Important study focusing on DNA methylation in gastric cancer.PubMedCrossRef
11.•
Wang K et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011;43:1219–23. First study to identify a new frequent mutaion in subtyping gastric cancer.PubMedCrossRef
12.•
Zang ZJ et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet. 2012;44:570–4. One of important researches using exome sequence in gastric cancer.PubMedCrossRef
13.
Fukayama M. Epstein-Barr virus and gastric carcinoma. Pathol Int. 2010;60:337–50.PubMedCrossRef
14.
Zur Hausen A et al. Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis. J Clin Pathol. 2004;57:487–91.PubMedCentralPubMedCrossRef
15.
Imai S et al. Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. Proc Natl Acad Sci U S A. 1994;91:9131–5.PubMedCentralPubMedCrossRef
16.
Chang MS et al. CpG island methylation status in gastric carcinoma with and without infection of Epstein-Barr virus. Clin Cancer Res. 2006;12:2995–3002.PubMedCrossRef
17.
Chen J. Roles of the PI3K/Akt pathway in Epstein-Barr virus-induced cancers and therapeutic implications. World J Virol. 2012;1:154–61.PubMedCentralPubMedCrossRef
18.
Network TCGAR. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRef
19.
Byun DS et al. Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int J Cancer. 2003;104:318–27.PubMedCrossRef
20.
Murakami D et al. Expression of phosphorylated Akt (pAkt) in gastric carcinoma predicts prognosis and efficacy of chemotherapy. Gastric Cancer. 2007;10:45–51.PubMedCrossRef
21.
Li VS et al. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer. 2005;5:29.PubMedCentralPubMedCrossRef
22.
Velho S et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005;41:1649–54.PubMedCrossRef
23.
Okines AF et al. Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials. Eur J Cancer. 2013;49:2116–25.PubMedCrossRef
24.
Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway—beyond rapalogs. Oncotarget. 2010;1:530–43.PubMedCentralPubMed
25.
Eichhorn PJ et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68:9221–30.PubMedCentralPubMedCrossRef
26.
Manara MC et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res. 2010;16:530–40.PubMedCrossRef
27.
Ohtsu A et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31:3935–43.PubMedCrossRef
28.
Li J et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.PubMedCrossRef
29.
Kang GH et al. Epstein-Barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol. 2002;160:787–94.PubMedCentralPubMedCrossRef
30.
Hino R et al. Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res. 2009;69:2766–74.PubMedCrossRef
31.
Li M et al. Immunohistochemical expression of mTOR negatively correlates with PTEN expression in gastric carcinoma. Oncol Lett. 2012;4:1213–8.PubMedCentralPubMed
32.••
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. Excellent review article on tumor immune checkpoints in cancer.PubMedCrossRef
33.
Keir ME et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.PubMedCrossRef
34.
Wu C et al. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006;108:19–24.PubMedCrossRef
35.
Sunakawa Y et al. Genetic variants in tumor immune checkpoints as prognostic markers in patients (pts) with localized advanced gastric cancer (AGC). ASCO Meet Abstr. 2014;32:4018.
36.
Segal NH et al. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. ASCO Meet Abstr. 2014;32:3002.
37.
Grosso J, et al. Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). Journal of Clinical Oncology 2013;31.
38.
Herbst RS, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. Journal of Clinical Oncology 2013;31.
39.
Huang Y et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–6.PubMedCentralPubMedCrossRef
40.
Levine RL et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673–83.PubMedCrossRef
41.
Ferrand A et al. Involvement of JAK2 upstream of the PI 3-kinase in cell-cell adhesion regulation by gastrin. Exp Cell Res. 2004;301:128–38.PubMedCrossRef
42.
Ding L et al. MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2. Cell Res. 2010;20:784–93.PubMedCrossRef
43.
Zhou J et al. Human gastrin mRNA expression up-regulated by Helicobacter pylori CagA through MEK/ERK and JAK2-signaling pathways in gastric cancer cells. Gastric Cancer. 2011;14:322–31.PubMedCrossRef
44.
Yan HB et al. Reduced expression of the chromatin remodeling gene ARID1A enhances gastric cancer cell migration and invasion via downregulation of E-cadherin transcription. Carcinogenesis. 2014;35:867–76.PubMedCrossRef
45.
Wang DD et al. Decreased expression of the ARID1A gene is associated with poor prognosis in primary gastric cancer. PLoS One. 2012;7:e40364.PubMedCentralPubMedCrossRef
46.
Yamamoto H et al. Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer. World J Gastroenterol. 2012;18:2745–55.PubMedCentralPubMedCrossRef
47.
Oki E et al. Chemosensitivity and survival in gastric cancer patients with microsatellite instability. Ann Surg Oncol. 2009;16:2510–5.PubMedCrossRef
48.
Choi YY et al. Is microsatellite instability a prognostic marker in gastric cancer? A systematic review with meta-analysis. J Surg Oncol. 2014;110:129–35.PubMedCrossRef
49.
Tamura G et al. Microsatellite alterations in adenoma and differentiated adenocarcinoma of the stomach. Cancer Res. 1995;55:1933–6.PubMed
50.
Corso G et al. Oncogenic mutations in gastric cancer with microsatellite instability. Eur J Cancer. 2011;47:443–51.PubMedCrossRef
51.
Oliveira C et al. BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene. 2003;22:9192–6.PubMedCrossRef
52.
Lee SH et al. BRAF and KRAS mutations in stomach cancer. Oncogene. 2003;22:6942–5.PubMedCrossRef
53.
Ribic CM et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.PubMedCentralPubMedCrossRef
54.
Drotschmann K et al. DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers. Biol Chem. 2002;383:969–75.PubMedCrossRef
55.
Deng G et al. Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res. 1999;59:2029–33.PubMed
56.
Hall MC et al. DNA binding by yeast Mlh1 and Pms1: implications for DNA mismatch repair. Nucleic Acids Res. 2003;31:2025–34.PubMedCentralPubMedCrossRef
57.
Li GM. The role of mismatch repair in DNA damage-induced apoptosis. Oncol Res. 1999;11:393–400.PubMed
58.
Fink D et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 1996;56:4881–6.PubMed
59.
Li Y, et al. Predictive value of CHFR and MLH1 methylation in human gastric cancer. Gastric Cancer. 2014.
60.
Jaiswal BS et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell. 2013;23:603–17.PubMedCrossRef
61.
Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75.PubMedCentralPubMedCrossRef
62.
Gradishar WJ. Emerging approaches for treating HER2-positive metastatic breast cancer beyond trastuzumab. Ann Oncol. 2013;24:2492–500.PubMedCrossRef
63.
Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 2006;8:215.PubMedCentralPubMedCrossRef
64.
Warneke VS et al. Cohort study based on the seventh edition of the TNM classification for gastric cancer: proposal of a new staging system. J Clin Oncol. 2011;29:2364–71.PubMedCrossRef
65.
Chiaravalli AM et al. Histotype-based prognostic classification of gastric cancer. World J Gastroenterol. 2012;18:896–904.PubMedCentralPubMedCrossRef
66.
Guilford P et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–5.PubMedCrossRef
67.
Schneider BG et al. Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer. Int J Cancer. 2010;127:2588–97.PubMedCentralPubMedCrossRef
68.
Carothers AM et al. Deficient E-cadherin adhesion in C57BL/6J-Min/+ mice is associated with increased tyrosine kinase activity and RhoA-dependent actomyosin contractility. Exp Cell Res. 2006;312:387–400.PubMedCrossRef
69.
Palomero T et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46:166–70.PubMedCentralPubMedCrossRef
70.
Sakata-Yanagimoto M et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:171–5.PubMedCrossRef
71.
Kakiuchi M et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014;46:583–7.PubMedCrossRef
72.
Hildebrand JD, Taylor JM, Parsons JT. An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase. Mol Cell Biol. 1996;16:3169–78.PubMedCentralPubMed
73.
Khosravi-Far R et al. Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol. 1995;15:6443–53.PubMedCentralPubMed
74.
Niimi T et al. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. 2001;21:7380–90.PubMedCentralPubMedCrossRef
75.
Ueda J et al. Heterogeneous expression of claudin-4 in human colorectal cancer: decreased claudin-4 expression at the invasive front correlates cancer invasion and metastasis. Pathobiology. 2007;74:32–41.PubMedCrossRef
76.
Sanada Y et al. Down-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype. J Pathol. 2006;208:633–42.PubMedCrossRef
77.
Matsuda Y et al. Gastric and intestinal claudin expression at the invasive front of gastric carcinoma. Cancer Sci. 2007;98:1014–9.PubMedCrossRef
78.
Ajani JA, et al. Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): Secondary and subset analyses. J Clin Oncol. 2009;27.
79.
Yamada Y, et al. Impact of dihydropyrimidine dehydrogenase status of biopsy specimens on efficacy of irinotecan plus cisplatin, S-1, or 5-FU as first-line treatment of advanced gastric cancer patients in JCOG9912. J Clin Oncol. 2009;27.
80.
Sukawa Y et al. Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer. World J Gastroenterol. 2012;18:6577–86.PubMedCentralPubMedCrossRef
81.
Moutinho C et al. Epidermal growth factor receptor structural alterations in gastric cancer. BMC Cancer. 2008;8:10.PubMedCentralPubMedCrossRef
82.
Lemoine NR et al. Amplification and overexpression of the EGF receptor and c-erbB-2 proto-oncogenes in human stomach cancer. Br J Cancer. 1991;64:79–83.PubMedCentralPubMedCrossRef
83.
Smolen GA et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci U S A. 2006;103:2316–21.PubMedCentralPubMedCrossRef
84.
Arteaga CL. HER3 and mutant EGFR meet MET. Nat Med. 2007;13:675–7.PubMedCrossRef
85.
Lordick F et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:490–9.PubMedCrossRef
86.
Waddell T et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:481–9.PubMedCentralPubMedCrossRef
87.
Dragovich T et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006;24:4922–7.PubMedCrossRef
88.
Rojo F et al. Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol. 2006;24:4309–16.PubMedCrossRef
89.
Bang YJ et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.PubMedCrossRef
90.
Hecht JR, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): the TRIO-013/LOGiC Trial. Journal of Clinical Oncology 2013;31.
91.
Bang YJ. A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study. Journal of Clinical Oncology 2013;31
92.
Satoh T et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—a randomized, phase III study. J Clin Oncol. 2014;32:2039–49.PubMedCrossRef
93.
Ohtsu A et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968–76.PubMedCrossRef
94.
Van Cutsem E et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30:2119–27.PubMedCrossRef
95.
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;383:31–9.PubMedCrossRef
96.
Wilke H et al. RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE). J Clin Oncol. 2014;32.
97.
Yi JH et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer. 2012;106:1469–74.PubMedCentralPubMedCrossRef
98.
Sun W et al. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol. 2010;28:2947–51.PubMedCentralPubMedCrossRef
99.
Kang Y et al. Randomized phase II study of capecitabine and cisplatin with or without sorafenib in patients with metastatic gastric cancer: STARGATE study. Ann Oncol. 2014;25:iv210.CrossRef
100.
Shah MA et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS One. 2013;8:e54014.PubMedCentralPubMedCrossRef
101.
Cunningham D, et al. MetGastric: a randomized phase III study of onartuzumab (MetMAb) in combination with mFOLFOX6 in patients with metastatic HER2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. Journal of Clinical Oncology 2013;31.