Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer.
Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer.
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多灶性肺癌基因组异质性的同时进化扩展和约束
DOI：
10.1038/s41467-017-00963-0
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发表时间：
2017-10-10
影响因子：
16.6
通讯作者：
Zhuang G
中科院分区：
文献类型：
--
作者：
Ma P;Fu Y;Cai MC;Yan Y;Jing Y;Zhang S;Chen M;Wu J;Shen Y;Zhu L;Chen HZ;Gao WQ;Wang M;Gu Z;Bivona TG;Zhao X;Zhuang G
最近的基因组分析揭示了各种癌症之间的实质性肿瘤异质性。然而，目前尚不清楚基因组异质性是否以及如何在肿瘤演变过程中受到限制。在这里，我们对一个独特的多同步肺癌（MSLC）队列进行测序，以确定相同种系和环境背景下遗传驱动因素的相对多样性和一致性。我们发现，每个多中心原发性肿瘤都有不同的致癌改变，包括实验证明具有功能性和治疗靶向性的新突变。然而，功能研究表明，一个显着的约束致瘤途径的异质性遗传变异。这些结果表明，尽管细胞在肿瘤发生过程中所采取的突变特异性途径是随机的，但遗传轨迹可能受到关键信号通路功能收敛选择的限制。我们的研究结果强调了强大的进化压力，同时塑造了基因组多样性的扩张和约束，这一原则对理解肿瘤进化和优化治疗策略具有重要意义。
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable. However, functional studies show a strikingly constrained tumorigenic pathway underlying heterogeneous genetic variants. These results suggest that although the mutation-specific routes that cells take during oncogenesis are stochastic, genetic trajectories may be constrained by selection for functional convergence on key signaling pathways. Our findings highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
食管鳞状细胞癌的空间瘤内异质性和时间克隆进化
影响因子：
30.8
作者：
Hao, Jia-Jie;Lin, De-Chen;Dinh, Huy Q.;Mayakonda, Anand;Jiang, Yan-Yi;Chang, Chen;Jiang, Ye;Lu, Chen-Chen;Shi, Zhi-Zhou;Xu, Xin;Zhang, Yu;Cai, Yan;Wang, Jin-Wu;Zhan, Qi-Min;Wei, Wen-Qiang;Berrnan, Benjamin P.;Wang, Ming-Rong;Koeffler, H. Phillip
通讯作者：
Koeffler, H. Phillip
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E
DOI：
10.1126/science.1253462
发表时间：
2014-10-10
期刊：
Science (New York, N.Y.)
影响因子：
--
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
通讯作者：
Swanton C