《自然—遺傳學(xué)》上的兩份報(bào)告介紹了科學(xué)家針對(duì)82個(gè)小細(xì)胞肺癌樣本的外顯子組測(cè)序分析工作。他們?yōu)楦深A(yù)治療找到了數(shù)個(gè)潛在標(biāo)靶,。
小細(xì)胞肺癌（SCLC）是一種侵入性癌癥,，其腫瘤較難被發(fā)現(xiàn),。這種肺癌很少能通過(guò)手術(shù)治愈,，從而使得對(duì)腫瘤的基因組的系統(tǒng)性分析變得困難。這也是首次科學(xué)家得出82個(gè)SCLC樣本的外顯子組測(cè)序數(shù)據(jù)以及確定該癌癥內(nèi)發(fā)生周期性突變的基因,。
Roman Thomas等人對(duì)29個(gè)SCLC樣本的外顯子組進(jìn)行測(cè)序并找到了與組織蛋白改性有關(guān)的一些基因突變,。Somasekar Seshagiri、 Charles Rudin等人則分別對(duì)36個(gè)SCLC初期腫瘤和17個(gè)從SCLC腫瘤中獲取的細(xì)胞系的外顯子組進(jìn)行測(cè)序,。他們共鑒定出了22個(gè)重要的基因突變包括編碼激酶,、G蛋白偶聯(lián)受體和染色質(zhì)改性蛋白的基因在內(nèi)。他們還在27%的樣本中找到SOX2基因擴(kuò)增,，這意味著SOX2基因作為致癌基因在SCLC中扮演重要角色,。（生物谷Bioon.com）
doi:10.1038/ng.2405
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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
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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.
