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Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.

Publication ,  Journal Article
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 ...
Published in: Gastroenterology
September 2013

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.

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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

September 2013

Volume

145

Issue

3

Start / End Page

554 / 565

Location

United States

Related Subject Headings

  • Treatment Outcome
  • TOR Serine-Threonine Kinases
  • Survival Analysis
  • Stomach Neoplasms
  • Retrospective Studies
  • Regression Analysis
  • Proto-Oncogene Proteins c-akt
  • Phosphoinositide-3 Kinase Inhibitors
  • Models, Statistical
  • Middle Aged
 

Citation

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Lei, Z., Tan, I. B., Das, K., Deng, N., Zouridis, H., Pattison, S., … Rozen, S. G. (2013). Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology, 145(3), 554–565. https://doi.org/10.1053/j.gastro.2013.05.010
Lei, Zhengdeng, Iain Beehuat Tan, Kakoli Das, Niantao Deng, Hermioni Zouridis, Sharon Pattison, Clarinda Chua, et al. “Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.Gastroenterology 145, no. 3 (September 2013): 554–65. https://doi.org/10.1053/j.gastro.2013.05.010.
Lei Z, Tan IB, Das K, Deng N, Zouridis H, Pattison S, et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology. 2013 Sep;145(3):554–65.
Lei, Zhengdeng, et al. “Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.Gastroenterology, vol. 145, no. 3, Sept. 2013, pp. 554–65. Pubmed, doi:10.1053/j.gastro.2013.05.010.
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. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology. 2013 Sep;145(3):554–565.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

September 2013

Volume

145

Issue

3

Start / End Page

554 / 565

Location

United States

Related Subject Headings

  • Treatment Outcome
  • TOR Serine-Threonine Kinases
  • Survival Analysis
  • Stomach Neoplasms
  • Retrospective Studies
  • Regression Analysis
  • Proto-Oncogene Proteins c-akt
  • Phosphoinositide-3 Kinase Inhibitors
  • Models, Statistical
  • Middle Aged