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Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy

 Iain Beehuat Tan  ;  Tatiana Ivanova  ;  Kiat Hon Lim  ;  Chee Wee Ong  ;  Niantao Deng  ;  Julian Lee  ;  Sze Huey Tan  ;  Jeanie Wu  ;  Ming Hui Lee  ;  Chia Huey Ooi  ;  Sun Young Rha  ;  Wai Keong Wong  ;  Alex Boussioutas  ;  Khay Guan Yeoh  ;  Jimmy So  ;  Wei Peng Yong  ;  Akira Tsuburaya  ;  Heike Grabsch  ;  Han Chong Toh  ;  Steven Rozen  ;  Jae Ho Cheong  ;  Sung Hoon Noh  ;  Wei Kiat Wan  ;  Jaffer A. Ajani  ;  Ju-Seog Lee  ;  Manuel Salto Tellez  ;  Patrick Tan 
 GASTROENTEROLOGY, Vol.141(2) : 476-485.e11, 2011 
Journal Title
Issue Date
Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/metabolism* ; Cadherins/metabolism* ; Cisplatin/therapeutic use ; Female ; Fluorouracil/therapeutic use ; Galectin 4/metabolism* ; Gene Expression Profiling* ; Humans ; Kaplan-Meier Estimate ; Male ; Microarray Analysis ; Middle Aged ; Organoplatinum Compounds/therapeutic use ; Prognosis ; Proportional Hazards Models ; Stomach Neoplasms/classification* ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/genetics* ; Stomach Neoplasms/pathology ; Survival Rate ; Young Adult
Microarray Analysis ; Pharmacogenomics ; mRNA ; Stomach ; Carcinogenesis
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Noh, Sung Hoon(노성훈) ORCID logo https://orcid.org/0000-0003-4386-6886
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
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