《自然—遗传学》上的两份报告介绍了科学家针对82个小细胞肺癌样本的外显子组测序分析工作。他们为干预治疗找到了数个潜在标靶。
小细胞肺癌（SCLC）是一种侵入性癌症，其肿瘤较难被发现。这种肺癌很少能通过手术治愈，从而使得对肿瘤的基因组的系统性分析变得困难。这也是首次科学家得出82个SCLC样本的外显子组测序数据以及确定该癌症内发生周期性突变的基因。
Roman Thomas等人对29个SCLC样本的外显子组进行测序并找到了与组织蛋白改性有关的一些基因突变。Somasekar Seshagiri、 Charles Rudin等人则分别对36个SCLC初期肿瘤和17个从SCLC肿瘤中获取的细胞系的外显子组进行测序。他们共鉴定出了22个重要的基因突变包括编码激酶、G蛋白偶联受体和染色质改性蛋白的基因在内。他们还在27%的样本中找到SOX2基因扩增，这意味着SOX2基因作为致癌基因在SCLC中扮演重要角色。（生物谷Bioon.com）
doi:10.1038/ng.2405
PMC:
PMID:
Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer
Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, Rivers CS, Foo CK, Bhatt D, Stinson J, Gnad F, Haverty PM, Gentleman R, Chaudhuri S, Janakiraman V, Jaiswal BS, Parikh C, Yuan W, Zhang Z, Koeppen H, Wu TD, Stern HM, Yauch RL, Huffman KE, Paskulin DD, Illei PB, Varella-Garcia M, Gazdar AF, de Sauvage FJ, Bourgon R, Minna JD, Brock MV, Seshagiri S.
Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in ～27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention.
doi:10.1038/ng.2396
PMC:
PMID:
Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
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, B?hm 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, S?nger 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.
Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 ± 1 protein-changing mutations per million base pairs. 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 the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, 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 Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
