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A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.

Publication ,  Journal Article
Deng, N; Goh, LK; Wang, H; Das, K; Tao, J; Tan, IB; Zhang, S; Lee, M; Wu, J; Lim, KH; Lei, Z; Goh, G; Lim, Q-Y; Tan, AL-K; Sin Poh, DY ...
Published in: Gut
May 2012

OBJECTIVE: Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers. DESIGN: Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. RESULTS: 22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers. CONCLUSION: The study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies.

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Published In

Gut

DOI

EISSN

1468-3288

Publication Date

May 2012

Volume

61

Issue

5

Start / End Page

673 / 684

Location

England

Related Subject Headings

  • ras Proteins
  • Stomach Neoplasms
  • Receptor, erbB-2
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins
  • Proportional Hazards Models
  • Polymorphism, Single Nucleotide
 

Citation

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Deng, N., Goh, L. K., Wang, H., Das, K., Tao, J., Tan, I. B., … Tan, P. (2012). A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut, 61(5), 673–684. https://doi.org/10.1136/gutjnl-2011-301839
Deng, Niantao, Liang Kee Goh, Hannah Wang, Kakoli Das, Jiong Tao, Iain Beehuat Tan, Shenli Zhang, et al. “A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.Gut 61, no. 5 (May 2012): 673–84. https://doi.org/10.1136/gutjnl-2011-301839.
Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, Zhang S, Lee M, Wu J, Lim KH, Lei Z, Goh G, Lim Q-Y, Tan AL-K, Sin Poh DY, Riahi S, Bell S, Shi MM, Linnartz R, Zhu F, Yeoh KG, Toh HC, Yong WP, Cheong HC, Rha SY, Boussioutas A, Grabsch H, Rozen S, Tan P. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012 May;61(5):673–684.

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

May 2012

Volume

61

Issue

5

Start / End Page

673 / 684

Location

England

Related Subject Headings

  • ras Proteins
  • Stomach Neoplasms
  • Receptor, erbB-2
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins
  • Proportional Hazards Models
  • Polymorphism, Single Nucleotide