Comprehensive genomic profiles of small cell lung cancer.
Comprehensive genomic profiles of small cell lung cancer.
复制标题
DOI：
10.1038/nature14664
复制
发表时间：
2015-08-06
期刊：
影响因子：
64.8
通讯作者：
Thomas RK
中科院分区：
文献类型：
--
作者：
George J;Lim JS;Jang SJ;Cun Y;Ozretić L;Kong G;Leenders F;Lu X;Fernández-Cuesta L;Bosco G;Müller C;Dahmen I;Jahchan NS;Park KS;Yang D;Karnezis AN;Vaka D;Torres A;Wang MS;Korbel JO;Menon R;Chun SM;Kim D;Wilkerson M;Hayes N;Engelmann D;Pützer B;Bos M;Michels S;Vlasic I;Seidel D;Pinther B;Schaub P;Becker C;Altmüller J;Yokota J;Kohno T;Iwakawa R;Tsuta K;Noguchi M;Muley T;Hoffmann H;Schnabel PA;Petersen I;Chen Y;Soltermann A;Tischler V;Choi CM;Kim YH;Massion PP;Zou Y;Jovanovic D;Kontic M;Wright GM;Russell PA;Solomon B;Koch I;Lindner M;Muscarella LA;la Torre A;Field JK;Jakopovic M;Knezevic J;Castaños-Vélez E;Roz L;Pastorino U;Brustugun OT;Lund-Iversen M;Thunnissen E;Köhler J;Schuler M;Botling J;Sandelin M;Sanchez-Cespedes M;Salvesen HB;Achter V;Lang U;Bogus M;Schneider PM;Zander T;Ansén S;Hallek M;Wolf J;Vingron M;Yatabe Y;Travis WD;Nürnberg P;Reinhardt C;Perner S;Heukamp L;Büttner R;Haas SA;Brambilla E;Peifer M;Sage J;Thomas RK
我们已经对110种小细胞肺癌（SCLC）的基因组进行了测序，SCLC是人类最致命的癌症之一。在几乎所有分析的肿瘤中，我们发现TP 53和RB 1的双等位基因失活，有时是通过复杂的基因组重排。两个肿瘤与野生型RB 1的chromothripsis导致细胞周期蛋白D1（由CCND 1基因编码）的过度表达的证据，揭示了Rb 1失调的替代机制。因此，肿瘤抑制因子TP 53和RB 1的丢失在SCLC中是强制性的。我们发现TP 73的体细胞基因组重排产生了该基因的致癌版本TP 73 Δ ex 2/3。在极少数情况下，SCLC肿瘤表现出激酶基因突变，为个体患者提供了可能的治疗机会。最后，我们在25%的人SCLC中观察到NOTCH家族基因的失活突变。因此，在临床前SCLC小鼠模型中Notch信号传导的激活显著减少了肿瘤的数量并延长了突变小鼠的存活期。此外，神经内分泌基因的表达被废除的Notch活性在SCLC细胞。这项对SCLC体细胞基因组改变的首次全面研究揭示了几个关键的生物学过程，并确定了这种高度致命的癌症形式的候选治疗靶点。
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.