Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.
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DOI：
10.1038/ng.3990
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发表时间：
2017-12
期刊：
影响因子：
30.8
通讯作者：
Bivona TG
中科院分区：
文献类型：
--
作者：
Blakely CM;Watkins TBK;Wu W;Gini B;Chabon JJ;McCoach CE;McGranahan N;Wilson GA;Birkbak NJ;Olivas VR;Rotow J;Maynard A;Wang V;Gubens MA;Banks KC;Lanman RB;Caulin AF;St John J;Cordero AR;Giannikopoulos P;Simmons AD;Mack PC;Gandara DR;Husain H;Doebele RC;Riess JW;Diehn M;Swanton C;Bivona TG
现代癌症治疗的广泛方法是鉴定单个致癌驱动基因并靶向其突变蛋白产物（例如EGFR突变型肺癌中的EGFR抑制剂治疗）。然而，基因驱动的对靶向治疗的耐药性限制了患者的生存。通过对1122个EGFR突变型肺癌无细胞DNA样本的基因组分析和对7个纵向收集的EGFR突变型肺癌患者的肿瘤样本的全外显子组分析，我们确定了大多数晚期EGFR突变型肺癌中存在的关键共发致癌事件。我们定义了限制EGFR抑制剂反应的新途径，包括WNT/β-catenin和细胞周期基因（例如CDK 4，CDK 6）改变。肿瘤基因组复杂性随着EGFR抑制剂治疗和CTNNB 1和PIK 3CA中共同发生的改变而增加，表现出协同促进肿瘤转移或限制EGFR抑制剂应答的非冗余功能。这项研究挑战了流行的单基因驱动癌基因观点，并将临床结果与晚期EGFR突变型肺癌患者中共同发生的遗传改变联系起来。
A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant protein product (e.g. EGFR inhibitor treatment in EGFR-mutant lung cancers). However, genetically-driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1122 EGFR-mutant lung cancer cell-free DNA samples and whole exome analysis of seven longitudinally collected tumor samples from an EGFR-mutant lung cancer patient, we identify critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We define new pathways limiting EGFR inhibitor response, including WNT/β-catenin and cell cycle gene (e.g. CDK4, CDK6) alterations. Tumor genomic complexity increases with EGFR inhibitor treatment and co-occurring alterations in CTNNB1, and PIK3CA exhibit non-redundant functions that cooperatively promote tumor metastasis or limit EGFR inhibitor response. This study challenges the prevailing single-gene driver oncogene view and links clinical outcomes to co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancer patients.
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影响因子：
16.6
作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
通讯作者：
Diehn M
影响因子：
11.2
作者：
Eberlein CA;Stetson D;Markovets AA;Al-Kadhimi KJ;Lai Z;Fisher PR;Meador CB;Spitzler P;Ichihara E;Ross SJ;Ahdesmaki MJ;Ahmed A;Ratcliffe LE;O'Brien EL;Barnes CH;Brown H;Smith PD;Dry JR;Beran G;Thress KS;Dougherty B;Pao W;Cross DA
通讯作者：
Cross DA
影响因子：
20.4
作者：
Ho, Chao-Chi;Liao, Wei-Yu;Yang, James Chih-Hsin
通讯作者：
Yang, James Chih-Hsin
影响因子：
158.5
作者：
Sequist, L. V.;Soria, J-C;Camidge, D. R.
通讯作者：
Camidge, D. R.
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