Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.
Journal Article (Journal Article;Multicenter Study)
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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Full Text
Duke Authors
Cited Authors
- Lei, Z; Tan, IB; Das, K; Deng, N; Zouridis, H; Pattison, S; Chua, C; Feng, Z; Guan, YK; Ooi, CH; Ivanova, T; Zhang, S; Lee, M; Wu, J; Ngo, A; Manesh, S; Tan, E; Teh, BT; So, JBY; Goh, LK; Boussioutas, A; Lim, TKH; Flotow, H; Tan, P; Rozen, SG
Published Date
- September 2013
Published In
Volume / Issue
- 145 / 3
Start / End Page
- 554 - 565
PubMed ID
- 23684942
Electronic International Standard Serial Number (EISSN)
- 1528-0012
Digital Object Identifier (DOI)
- 10.1053/j.gastro.2013.05.010
Language
- eng
Conference Location
- United States