A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.
A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.
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DOI：
10.1136/gutjnl-2011-301839
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发表时间：
2012-05
期刊：
影响因子：
24.5
通讯作者：
Tan P
中科院分区：
文献类型：
--
作者：
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 QY;Tan AL;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
胃癌是一种主要的胃肠道恶性肿瘤，靶向治疗正在成为治疗选择。本研究旨在通过对一大组胃癌进行全面的基因组分析，确定胃癌中最常见的分子靶点，并阐明这些靶点之间的排他性和共现性的系统模式。使用高分辨率的单核苷酸多态性阵列，拷贝数的改变，在一组233胃癌（193原发性肿瘤，40细胞系）和98个主要匹配的胃非恶性样本。对于选定的改变，评估其对基因表达和临床结果的影响。22复发局灶性改变（13扩增和9缺失）进行了鉴定。这些包括已知的靶点（FGFR 2，ERBB 2）和胃癌中的新基因（KLF 5，GATA 6）。受体酪氨酸激酶（RTK）/RAS改变在胃癌中是常见的。这项研究还首次证明，这些改变以相互排斥的方式发生，KRAS基因扩增突出了临床相关但以前未被充分认识的胃癌亚组。还显示FGFR 2扩增的胃癌对dovitinib敏感，dovitinib是一种口服生物可利用的FGFR/VEGFR靶向药物，可能代表FGFR 2扩增的胃癌的亚型特异性治疗。该研究表明存在五个不同的胃癌患者亚组，由标记基因组改变FGFR 2（9%的肿瘤），KRAS（9%），EGFR（8%），ERBB 2（7%）和MET（4%）定义。总的来说，这些亚组表明至少37%的胃癌患者可能通过RTK/RAS定向疗法治疗。
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. 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. 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. 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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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Dey, Julien H.;Bianchi, Fabrizio;Hynes, Nancy E.
通讯作者：
Hynes, Nancy E.
DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
DOI：
10.1016/s0140-6736(09)60617-6
发表时间：
2009-08-08
期刊：
Lancet (London, England)
影响因子：
--
作者：
Hartgrink HH;Jansen EP;van Grieken NC;van de Velde CJ
通讯作者：
van de Velde CJ
影响因子：
28.2
作者：
Kim ES;Herbst RS;Wistuba II;Lee JJ;Blumenschein GR Jr;Tsao A;Stewart DJ;Hicks ME;Erasmus J Jr;Gupta S;Alden CM;Liu S;Tang X;Khuri FR;Tran HT;Johnson BE;Heymach JV;Mao L;Fossella F;Kies MS;Papadimitrakopoulou V;Davis SE;Lippman SM;Hong WK
通讯作者：
Hong WK