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

被引:538
作者
Deng, Niantao [1 ,2 ]
Goh, Liang Kee [1 ,3 ,4 ]
Wang, Hannah [1 ]
Das, Kakoli [1 ]
Tao, Jiong [1 ,5 ]
Tan, Iain Beehuat [1 ,2 ,4 ]
Zhang, Shenli [1 ]
Lee, Minghui
Wu, Jeanie
Lim, Kiat Hon [6 ]
Lei, Zhengdeng
Goh, Glenn [1 ]
Lim, Qing-Yan [7 ]
Tan, Angie Lay-Keng [1 ]
Poh, Dianne Yu Sin [1 ]
Riahi, Sudep [8 ]
Bell, Sandra [8 ]
Shi, Michael M. [9 ]
Linnartz, Ronald [9 ]
Zhu, Feng [10 ]
Yeoh, Khay Guan [10 ]
Toh, Han Chong [4 ]
Yong, Wei Peng [11 ]
Cheong, Hyun Cheol [12 ]
Rha, Sun Young [12 ]
Boussioutas, Alex [13 ]
Grabsch, Heike [14 ]
Rozen, Steve
Tan, Patrick [1 ,15 ,16 ]
机构
[1] Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore 169857, Singapore
[2] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore
[3] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore
[4] Natl Canc Ctr, Div Med Oncol, Singapore, Singapore
[5] Natl Univ Singapore, Dept Physiol, Singapore 117548, Singapore
[6] Singapore Gen Hosp, Dept Pathol, Singapore 0316, Singapore
[7] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore
[8] Leeds Inst Mol Med, Sect Ophthalmol & Neurosci, Leeds, W Yorkshire, England
[9] Novartis Oncol, E Hanover, NJ USA
[10] Natl Univ Hlth Syst, Dept Med, Singapore, Singapore
[11] Natl Univ Hlth Syst, Natl Canc Inst Singapore, Singapore, Singapore
[12] Yonsei Canc Ctr, Dept Internal Med, Yonsei, South Korea
[13] Peter MacCallum Canc Ctr, Canc Genom & Biochem Lab, Melbourne, Vic, Australia
[14] Leeds Inst Mol Med, Dept Pathol & Tumour Biol, Leeds, W Yorkshire, England
[15] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore
[16] Genome Inst Singapore, Singapore, Singapore
关键词
GROWTH-FACTOR RECEPTOR; LINEAGE-SURVIVAL ONCOGENE; TYROSINE KINASE INHIBITOR; COPY-NUMBER; TRASTUZUMAB RESISTANCE; ACQUIRED-RESISTANCE; GENETIC ALTERATIONS; LUNG; AMPLIFICATION; EXPRESSION;
D O I
10.1136/gutjnl-2011-301839
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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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收藏
页码:673 / 684
页数:12
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