Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
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DOI：
10.1126/science.1253462
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发表时间：
2014-10-10
期刊：
影响因子：
--
通讯作者：
Swanton C
中科院分区：
文献类型：
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作者：
de Bruin EC;McGranahan N;Mitter R;Salm M;Wedge DC;Yates L;Jamal-Hanjani M;Shafi S;Murugaesu N;Rowan AJ;Grönroos E;Muhammad MA;Horswell S;Gerlinger M;Varela I;Jones D;Marshall J;Voet T;Van Loo P;Rassl DM;Rintoul RC;Janes SM;Lee SM;Forster M;Ahmad T;Lawrence D;Falzon M;Capitanio A;Harkins TT;Lee CC;Tom W;Teefe E;Chen SC;Begum S;Rabinowitz A;Phillimore B;Spencer-Dene B;Stamp G;Szallasi Z;Matthews N;Stewart A;Campbell P;Swanton C
对人类非小细胞肺癌(NSCLC)演变过程中基因组变化的时空解剖可能有助于阐明其预后不良的基础。我们从7个可操作的NSCLC中测序了25个空间上不同的区域，并发现了分支进化的证据，亚克隆多样化前后出现了驱动突变。与APOBEC胞苷脱氨酶活性相关的拷贝数改变、易位和突变存在明显的肿瘤内异质性。尽管持续接触致癌物，吸烟者的肿瘤随着时间的推移显示与吸烟相关的突变相对减少，同时与APOBEC相关的突变增加。在前吸烟者的肿瘤中，在亚克隆多样化之前，基因组加倍发生在吸烟特征的背景下，这表明在临床检测之前，肿瘤潜伏期很长。区域分离的驱动程序突变，加上基因组不稳定过程的无情和异质性，可能会混淆非小细胞肺癌的治疗成功。
Spatial and temporal dissection of the genomic changes occurring during the evolution of human non–small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.