Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis.
Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis.
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DOI：
10.1158/0008-5472.can-11-3893
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发表时间：
2012-09-01
期刊：
影响因子：
11.2
通讯作者：
Bass AJ
中科院分区：
文献类型：
--
作者：
Dulak AM;Schumacher SE;van Lieshout J;Imamura Y;Fox C;Shim B;Ramos AH;Saksena G;Baca SC;Baselga J;Tabernero J;Barretina J;Enzinger PC;Corso G;Roviello F;Lin L;Bandla S;Luketich JD;Pennathur A;Meyerson M;Ogino S;Shivdasani RA;Beer DG;Godfrey TE;Beroukhim R;Bass AJ
为了改进诊断和治疗方法，有必要更详细地了解驱动胃肠腺癌的体细胞遗传事件。利用高密度基因组分析阵列的数据，我们对486例胃肠腺癌（包括296例食管癌和胃癌）中的体细胞拷贝数变异（SCNA）进行了分析。局灶性扩增在胃/食管腺癌中比在结直肠肿瘤中更为普遍。我们确定了64个具有显著反复扩增和缺失的区域，其中一些区域在被检测的腺癌类型中是共有的，而另一些则是独特的。在37%的胃/食管肿瘤中发现了扩增基因，包括可作为治疗靶点的激酶，如ERBB2、FGFR1、FGFR2、EGFR和MET，这表明基因组扩增作为生物标志物在指导胃癌和食管癌治疗方面可能具有潜在用途，因为与结直肠癌相比，针对胃癌和食管癌的靶向治疗发展相对滞后。扩增位点涉及已知与致癌作用有关的基因，但也指向可能含有新型癌基因的区域，包括在15%的食管肿瘤中发现的一个反复缺失区域，其中涉及Runt转录因子亚基RUNX1，组织培养中的功能实验也证实了这一点。总之，我们的研究结果明确了各种肠道来源腺癌共有的和独特的基因组特征，可能为靶向治疗干预提供新的机会。
A more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy. Using data from high-density genomic profiling arrays, we conducted an analysis of somatic copy-number aberrations (SCNAs) in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers. Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors. We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined. Amplified genes were noted in 37% of gastric/esophageal tumors, including in therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting the potential utility of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared to colorectal cancers. Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture. Together, our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions.