A landscape of driver mutations in melanoma.
A landscape of driver mutations in melanoma.
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DOI：
10.1016/j.cell.2012.06.024
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发表时间：
2012-07-20
期刊：
影响因子：
64.5
通讯作者：
Chin L
中科院分区：
文献类型：
--
作者：
Hodis E;Watson IR;Kryukov GV;Arold ST;Imielinski M;Theurillat JP;Nickerson E;Auclair D;Li L;Place C;Dicara D;Ramos AH;Lawrence MS;Cibulskis K;Sivachenko A;Voet D;Saksena G;Stransky N;Onofrio RC;Winckler W;Ardlie K;Wagle N;Wargo J;Chong K;Morton DL;Stemke-Hale K;Chen G;Noble M;Meyerson M;Ladbury JE;Davies MA;Gershenwald JE;Wagner SN;Hoon DS;Schadendorf D;Lander ES;Gabriel SB;Getz G;Garraway LA;Chin L
尽管最近对黑色素瘤遗传学有了深入的了解，但对驱动突变的系统调查受到致癌紫外线（UV）暴露引起的大量乘客突变的挑战。我们开发了一个基于排列的框架来解决这一挑战，采用内含子序列的突变数据来控制每个基因基础上的乘客突变负荷。通过这种方法分析大规模黑色素瘤外显子组数据发现了六种新的黑色素瘤基因（PPP 6C，RAC 1，SNX 31，TACC 1，STK 19和ARID 2），其中三种-RAC 1，PPP 6C和STK 19-具有复发性和潜在的靶向突变。与染色体拷贝数数据的整合使驱动突变的情况背景化，提供了BRAF和NRAS驱动的黑色素瘤以及没有已知NRAS/BRAF突变的黑色素瘤的致癌见解。景观也澄清了突变的基础RB和p53通路失调，在这种恶性肿瘤。最后，驱动突变谱为紫外线在黑色素瘤发病机制中的直接致突变作用提供了明确的基因组证据。
Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.
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DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
11.2
作者：
Cully, M;Shiu, J;Mak, TW
通讯作者：
Mak, TW
影响因子：
64.8
作者：
Cho, Uhn Soo;Xu, Wenqing
通讯作者：
Xu, Wenqing
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