Background & Aims
Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents.
We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes. We developed a classifier for these subtypes and validated it in 70 tumors from a different population. We identified distinct genomic and epigenomic properties of the subtypes. We determined drug sensitivities of the subtypes in primary tumors using clinical survival data, and in cell lines through high-throughput drug screening.
We identified 3 subtypes of gastric adenocarcinoma: proliferative, metabolic, and mesenchymal. Tumors of the proliferative subtype had high levels of genomic instability, TP53 mutations, and DNA hypomethylation. Cancer cells of the metabolic subtype were more sensitive to 5-fluorouracil than the other subtypes. Furthermore, in 2 independent groups of patients, those with tumors of the metabolic subtype appeared to have greater benefits with 5-fluorouracil treatment. Tumors of the mesenchymal subtype contain cells with features of cancer stem cells, and cell lines of this subtype are particularly sensitive to phosphatidylinositol 3-kinase−AKT−mTOR inhibitors in vitro.
Based on gene expression patterns, we classified gastric cancers into 3 subtypes, and validated these in an independent set of tumors. The subgroups have differences in molecular and genetic features and response to therapy; this information might be used to select specific treatment approaches for patients with gastric cancer.
ZHENGDENG LEI,1,2 IAIN BEEHUAT TAN,2,3,4 KAKOLI DAS,2 NIANTAO DENG,2,3 HERMIONI ZOURIDIS,2 SHARON PATTISON,5 CLARINDA CHUA,6 ZHU FENG,6 YEOH KHAY GUAN,6,7 CHIA HUEY OOI,2 TATIANA IVANOVA,8 SHENLI ZHANG,2 MINGHUI LEE,8 JEANIE WU,8 ANNA NGO,9 SRAVANTHY MANESH,9 ELISABETH TAN,1,2 BIN TEAN TEH,2,10 JIMMY BOK YAN SO,11 LIANG KEE GOH,2 ALEX BOUSSIOUTAS,5,12,13,14 TONY KIAT HON LIM,15 HORST FLOTOW,9 PATRICK TAN,2,8,16,17, * and STEVEN G. ROZEN1,2, *
* = Co-corresponding Authors
1Centre for Computational Biology; 2Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore;
3National University of Singapore Graduate School for Integrative Sciences and Engineering; 4Department of Medical Oncology, National Cancer Centre Singapore, Singapore;
5Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Victoria, Australia;
6Department of Medicine, 7Department of Gastroenterology and Hepatology, National University Health System, Singapore;
8Cellular and Molecular Research, National Cancer Centre Singapore, Singapore;
9The Experimental Therapeutics Centre, 17Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore;
10National Cancer Centre Singapore – Van Andel Research Institute Translational Research Laboratory, National Cancer Centre Singapore, Singapore;
11Department of Surgery, National University Health System, Singapore;
12Department of Medicine, 13Department of Gastroenterology, Royal Melbourne Hospital, Victoria, Australia;
14Department of Gastroenterology, Western Hospital, Victoria, Australia;
15Department of Pathology, Singapore General Hospital, Singapore;
16Cancer Science Institute of Singapore, National University of Singapore, Singapore