Gastroenterology

Gastroenterology

Volume 141, Issue 2, August 2011, Pages 476-485.e11
Gastroenterology

Original Research
Clinical—Alimentary Tract
Intrinsic Subtypes of Gastric Cancer, Based on Gene Expression Pattern, Predict Survival and Respond Differently to Chemotherapy

https://doi.org/10.1053/j.gastro.2011.04.042Get rights and content

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-fluorouracil–based 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.

Section snippets

GC Cell Lines

GC cell lines were obtained from commercial sources or collaborators and cultured as recommended (Supplementary Materials and Methods). Cell proliferation assays were performed using a tetrazolium compound–based colorimetric method (Supplementary Materials and Methods).

Patient Cohorts and Clinical Characteristics

Four independent patient cohorts were analyzed (N = 521); cohort 1 (SG) included 200 patients from the National Cancer Centre Singapore in Singapore, cohort 2 (AU) included 70 patients from Peter MacCallum Cancer Centre in

Genomic Analysis of GC Cell Lines Reveals 2 Major Intrinsic Subclasses

We performed gene expression profiling for a panel of 37 GC cell lines. To identify pervasive and thereby “intrinsic” gene expression differences across the cell lines, we analyzed the expression data using 4 different unsupervised and unbiased clustering techniques (hierarchical clustering, silhouette plot analysis,22 nonnegative matrix factorization,23 and principal components analysis). Two major intrinsic subtypes were identified by hierarchical clustering (Figure 1A). The robustness of the

Discussion

In this study, we report the discovery of 2 genomic subtypes of GC using profiles initially derived from GC cell lines. Because cancer cell lines are devoid of stroma, vasculature, and immune cells, we reasoned that comparing signatures between cell lines would be more likely to reflect intrinsic differences between tumor cells, minimizing potentially confounding effects from neighboring noncancer tissues. The validity of the cell line–based approach is supported by similar studies in other

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    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.

    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.

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