Background & Aims: Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs. Methods: We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed. Results: Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracilbased therapy. Conclusions: Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.
Bibliographical noteFunding Information:
Funding Supported by grants from BMRC 05/1/31/19/423 (to P.T.), NMRC grant TCR/001/2007 (to P.T.), and a Duke-National University of Singapore core grant (to P.T.). Also supported by grants from the National Research Foundation of Singapore and American Society of Clinical Oncology Conquer Cancer Foundation (to I.B.T.). Cohort 3 was funded by NIH R01 (to J.-S.L.). J.A.A. is supported by a program grant from the University of Texas MD Anderson Cancer Center ; the Park, Dallas, Cantu, and Smith families; Kevin and Sultan funds; and Rivercreek and Schecter Private Foundations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest The authors disclose the following: As mandated for research projects funded by the Singapore government, a patent application covering this work has been filed by Exploit Technologies Pte Ltd, the intellectual property arm of the Agency for Science Technology and Research, Singapore.
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