Primary Colorectal Cancers and Their Subsequent Hepatic Metastases Are Genetically Different: Implications for Selection of Patients for Targeted Treatment
Primary Colorectal Cancers and Their Subsequent Hepatic Metastases Are Genetically Different: Implications for Selection of Patients for Targeted Treatment
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DOI：
10.1158/1078-0432.ccr-11-1965
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发表时间：
2012-02-01
影响因子：
11.5
通讯作者：
Voest, Emile E.
中科院分区：
文献类型：
--
作者：
Vermaat, Joost S.;Nijman, Isaac J.;Voest, Emile E.
目的：在dna引导的个体化癌症治疗时代，对重要组织进行预测分析至关重要。在这里，我们分析了原发性结直肠癌（CRC）及其相应的肝转移之间的遗传差异。实验设计：对21例结直肠癌患者的原发性结直肠癌和随后的肝转移进行了靶向深度测序，这些DNA是从福尔马林固定石蜡包埋的存档材料中分离出来的。结果：我们已经询问了设计的“癌症迷你基因组”的遗传构成，该基因组由1264个与癌症相关途径相关的基因的所有外显子组成。总共在1174个和667个基因中分别鉴定出6696个已知变异和1305个新变异，其中包括817个可能改变蛋白质功能的变异。平均而言，83个（SD = 69）潜在功能受损变异在转移中获得，70个（SD = 48）变异丢失，表明原发肿瘤和肝转移在遗传上存在显著差异。除了KRAS、BRAF、KDR、FLT1、PTEN、PI3KCA等基因的新变异和已知变异外，还检测到EGER/PI3K/ vegf通路及其他通路（mTOR、TGF β等）上/下游基因的畸变，可能影响治疗反应性。从原发肿瘤切除到转移（N = 11）之间的化疗没有进一步增加遗传变异的数量。结论：我们的研究表明肝转移的遗传特征与原发性结直肠癌不同。因此，在研究靶向治疗的研究中，治疗的选择应该理想地基于转移的遗传特性，而不是基于原发肿瘤的遗传特性。临床癌症研究；18 (3);688 - 99。AACR (C) 2011。
Purpose: In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters. Here, we analyzed genetic differences between primary colorectal adenocarcinomas (CRC) and their respective hepatic metastasis.Experimental Design: The primary CRC and the subsequent hepatic metastasis of 21 patients with CRC were analyzed using targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material.Results: We have interrogated the genetic constitution of a designed "Cancer Mini-Genome" consisting of all exons of 1,264 genes associated with pathways relevant to cancer. In total, 6,696 known and 1,305 novel variations were identified in 1,174 and 667 genes, respectively, including 817 variants that potentially altered protein function. On average, 83 (SD = 69) potentially function-impairing variations were gained in the metastasis and 70 (SD = 48) variations were lost, showing that the primary tumor and hepatic metastasis are genetically significantly different. Besides novel and known variations in genes such as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, aberrations in the up/downstream genes of EGER/PI3K/VEGF-pathways and other pathways (mTOR, TGF beta, etc.) were also detected, potentially influencing therapeutic responsiveness. Chemotherapy between removal of the primary tumor and the metastasis (N = 11) did not further increase the amount of genetic variation.Conclusion: Our study indicates that the genetic characteristics of the hepatic metastases are different from those of the primary CRC tumor. As a consequence, the choice of treatment in studies investigating targeted therapies should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor. Clin Cancer Res; 18(3); 688-99. (C)2011 AACR.