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 RozenJae Ho Cheong, Sung Hoon Noh, Wei Kiat Wan, Jaffer A. Ajani, Juseog Lee, Manuel Salto Tellez, Patrick Tan

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)476-485.e11
JournalGastroenterology
Volume141
Issue number2
DOIs
Publication statusPublished - 2011 Aug

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Stomach Neoplasms
oxaliplatin
Gene Expression
Drug Therapy
Survival
Cell Line
Gastrin-Secreting Cells
Fluorouracil
Cisplatin
Galectin 4
Neoplasm Genes
Standard of Care
Transcriptome
Pharmaceutical Preparations
Multivariate Analysis
Therapeutics
Neoplasms

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Tan, Iain Beehuat ; Ivanova, Tatiana ; Lim, Kiat Hon ; Ong, Chee Wee ; Deng, Niantao ; Lee, Julian ; Tan, Sze Huey ; Wu, Jeanie ; Lee, Ming Hui ; Ooi, Chia Huey ; Rha, Sun Young ; Wong, Wai Keong ; Boussioutas, Alex ; Yeoh, Khay Guan ; So, Jimmy ; Yong, Wei Peng ; Tsuburaya, Akira ; Grabsch, Heike ; Toh, Han Chong ; Rozen, Steven ; Cheong, Jae Ho ; Noh, Sung Hoon ; Wan, Wei Kiat ; Ajani, Jaffer A. ; Lee, Juseog ; Tellez, Manuel Salto ; Tan, Patrick. / Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. In: Gastroenterology. 2011 ; Vol. 141, No. 2. pp. 476-485.e11.
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title = "Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy",
abstract = "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.",
author = "Tan, {Iain Beehuat} and Tatiana Ivanova and Lim, {Kiat Hon} and Ong, {Chee Wee} and Niantao Deng and Julian Lee and Tan, {Sze Huey} and Jeanie Wu and Lee, {Ming Hui} and Ooi, {Chia Huey} and Rha, {Sun Young} and Wong, {Wai Keong} and Alex Boussioutas and Yeoh, {Khay Guan} and Jimmy So and Yong, {Wei Peng} and Akira Tsuburaya and Heike Grabsch and Toh, {Han Chong} and Steven Rozen and Cheong, {Jae Ho} and Noh, {Sung Hoon} and Wan, {Wei Kiat} and Ajani, {Jaffer A.} and Juseog Lee and Tellez, {Manuel Salto} and Patrick Tan",
year = "2011",
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doi = "10.1053/j.gastro.2011.04.042",
language = "English",
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Tan, IB, Ivanova, T, Lim, KH, Ong, CW, Deng, N, Lee, J, Tan, SH, Wu, J, Lee, MH, Ooi, CH, Rha, SY, Wong, WK, Boussioutas, A, Yeoh, KG, So, J, Yong, WP, Tsuburaya, A, Grabsch, H, Toh, HC, Rozen, S, Cheong, JH, Noh, SH, Wan, WK, Ajani, JA, Lee, J, Tellez, MS & Tan, P 2011, 'Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy', Gastroenterology, vol. 141, no. 2, pp. 476-485.e11. https://doi.org/10.1053/j.gastro.2011.04.042

Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. / Tan, Iain Beehuat; Ivanova, Tatiana; Lim, Kiat Hon; Ong, Chee Wee; Deng, Niantao; Lee, Julian; Tan, Sze Huey; Wu, Jeanie; Lee, Ming Hui; Ooi, Chia Huey; Rha, Sun Young; Wong, Wai Keong; Boussioutas, Alex; Yeoh, Khay Guan; So, Jimmy; Yong, Wei Peng; Tsuburaya, Akira; Grabsch, Heike; Toh, Han Chong; Rozen, Steven; Cheong, Jae Ho; Noh, Sung Hoon; Wan, Wei Kiat; Ajani, Jaffer A.; Lee, Juseog; Tellez, Manuel Salto; Tan, Patrick.

In: Gastroenterology, Vol. 141, No. 2, 08.2011, p. 476-485.e11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy

AU - Tan, Iain Beehuat

AU - Ivanova, Tatiana

AU - Lim, Kiat Hon

AU - Ong, Chee Wee

AU - Deng, Niantao

AU - Lee, Julian

AU - Tan, Sze Huey

AU - Wu, Jeanie

AU - Lee, Ming Hui

AU - Ooi, Chia Huey

AU - Rha, Sun Young

AU - Wong, Wai Keong

AU - Boussioutas, Alex

AU - Yeoh, Khay Guan

AU - So, Jimmy

AU - Yong, Wei Peng

AU - Tsuburaya, Akira

AU - Grabsch, Heike

AU - Toh, Han Chong

AU - Rozen, Steven

AU - Cheong, Jae Ho

AU - Noh, Sung Hoon

AU - Wan, Wei Kiat

AU - Ajani, Jaffer A.

AU - Lee, Juseog

AU - Tellez, Manuel Salto

AU - Tan, Patrick

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

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U2 - 10.1053/j.gastro.2011.04.042

DO - 10.1053/j.gastro.2011.04.042

M3 - Article

C2 - 21684283

AN - SCOPUS:80051486834

VL - 141

SP - 476-485.e11

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

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