Clonal architectures and driver mutations in metastatic melanomas.
Clonal architectures and driver mutations in metastatic melanomas.
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DOI：
10.1371/journal.pone.0111153
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Weber JS
中科院分区：
文献类型：
--
作者：
Ding L;Kim M;Kanchi KL;Dees ND;Lu C;Griffith M;Fenstermacher D;Sung H;Miller CA;Goetz B;Wendl MC;Griffith O;Cornelius LA;Linette GP;McMichael JF;Sondak VK;Fields RC;Ley TJ;Mulé JJ;Wilson RK;Weber JS
为了揭示黑色素瘤的克隆结构和相关的驱动基因突变，采用全基因组测序(WGS)和靶向延伸测序的方法对124例黑色素瘤病例进行了分析。使用13个WGS病例和另外15个配对扩展病例进行的显著突变的基因分析发现了已知的黑色素瘤基因，如BRAF、NRAS和CDKN2A，以及一个新的基因EphA3，以前与其他癌症类型有关。对另外96例患者的肿瘤进行的扩展研究发现，肿瘤抑制基因(TP53和RB1)、蛋白磷酸酶(例如PTEN、PTPRB、PTPRD和PTPRT)以及染色质重塑基因(例如ASXL3、ML12和ARID2)存在大量截断突变。对13例WGS患者的大多数转移瘤进行了基因突变的深度测序，发现了亚克隆。在13名WGS患者中，12名患者的有效突变表现出明显的紫外线特征，特征是在联嘧啶序列的3‘碱基上发生高频率的C->；T转变，而1名具有超突变表型的患者(MEL9)缺乏这一特征。值得注意的是，亚克隆突变特征分析表明，MEL9的建立克隆具有紫外线特征，而次级克隆没有，这表明来自同一肿瘤的两个克隆群体的突变机制不同。对2个黑色素瘤病例中来自不同地理位置的四个转移瘤的进一步分析揭示了系统发育关系，并强调了导致转移性肿瘤之间不同耐药性的基因改变。我们的研究表明，克隆性评估对于了解黑色素瘤的肿瘤病因和耐药性至关重要。
To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3′ base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
64.8
作者：
Berger, Michael F.;Hodis, Eran;Heffernan, Timothy P.;Deribe, Yonathan Lissanu;Lawrence, Michael S.;Protopopov, Alexei;Ivanova, Elena;Watson, Ian R.;Nickerson, Elizabeth;Ghosh, Papia;Zhang, Hailei;Zeid, Rhamy;Ren, Xiaojia;Cibulskis, Kristian;Sivachenko, Andrey Y.;Wagle, Nikhil;Sucker, Antje;Sougnez, Carrie;Onofrio, Robert;Ambrogio, Lauren;Auclair, Daniel;Fennell, Timothy;Carter, Scott L.;Drier, Yotam;Stojanov, Petar;Singer, Meredith A.;Voet, Douglas;Jing, Rui;Saksena, Gordon;Barretina, Jordi;Ramos, Alex H.;Pugh, Trevor J.;Stransky, Nicolas;Parkin, Melissa;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Wargo, Jennifer;Schadendorf, Dirk;Meyerson, Matthew;Gabriel, Stacey B.;Golub, Todd R.;Wagner, Stephan N.;Lander, Eric S.;Getz, Gad;Chin, Lynda;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
DOI：
10.1126/science.1229259
发表时间：
2013-02-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Huang FW;Hodis E;Xu MJ;Kryukov GV;Chin L;Garraway LA
通讯作者：
Garraway LA