Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.
Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.
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DOI：
10.1038/ng.2396
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发表时间：
2012-10
期刊：
影响因子：
30.8
通讯作者：
Thomas RK
中科院分区：
文献类型：
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作者：
Peifer M;Fernández-Cuesta L;Sos ML;George J;Seidel D;Kasper LH;Plenker D;Leenders F;Sun R;Zander T;Menon R;Koker M;Dahmen I;Müller C;Di Cerbo V;Schildhaus HU;Altmüller J;Baessmann I;Becker C;de Wilde B;Vandesompele J;Böhm D;Ansén S;Gabler F;Wilkening I;Heynck S;Heuckmann JM;Lu X;Carter SL;Cibulskis K;Banerji S;Getz G;Park KS;Rauh D;Grütter C;Fischer M;Pasqualucci L;Wright G;Wainer Z;Russell P;Petersen I;Chen Y;Stoelben E;Ludwig C;Schnabel P;Hoffmann H;Muley T;Brockmann M;Engel-Riedel W;Muscarella LA;Fazio VM;Groen H;Timens W;Sietsma H;Thunnissen E;Smit E;Heideman DA;Snijders PJ;Cappuzzo F;Ligorio C;Damiani S;Field J;Solberg S;Brustugun OT;Lund-Iversen M;Sänger J;Clement JH;Soltermann A;Moch H;Weder W;Solomon B;Soria JC;Validire P;Besse B;Brambilla E;Brambilla C;Lantuejoul S;Lorimier P;Schneider PM;Hallek M;Pao W;Meyerson M;Sage J;Shendure J;Schneider R;Büttner R;Wolf J;Nürnberg P;Perner S;Heukamp LC;Brindle PK;Haas S;Thomas RK
小细胞肺癌（SCLC）是一种侵袭性肺肿瘤亚型，生存率较差。我们对 29 个 SCLC 外显子组、两个基因组和 15 个转录组进行了测序，发现每百万碱基对有 7.4±1 个蛋白质改变突变的极高突变率。因此，我们对各种数据集进行了综合分析，以确定致病相关的突变基因。在所有病例中，我们都发现了 TP53 和 RB1 失活的证据，并确定了组蛋白修饰基因 CREBBP、EP300 和 MLL 中的反复突变。此外，我们观察到 PTEN、SLIT2 和 EPHA7 的突变，以及 FGFR1 酪氨酸激酶基因的局部扩增。最后，我们在 p53/Rb1 缺陷小鼠的 SCLC 肿瘤中检测到了许多在人类中发现的改变。我们的研究表明组蛋白修饰是 SCLC 的一个主要特征，揭示了潜在的治疗上易于处理的基因组改变，并为在高突变背景下鉴定生物学相关基因提供了一个通用的框架。
Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor survival. We sequenced 29 SCLC exomes, two genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in histone-modifying genes, CREBBP, EP300, and MLL. Furthermore, we observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from p53/Rb1-deficient mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genome alterations, and provides a generalizable framework for identification of biologically relevant genes in the context of high mutational background.