Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.
Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.
复制标题
DOI：
10.1038/ng.2359
复制
发表时间：
2012-09
期刊：
影响因子：
30.8
通讯作者：
Halaban, Ruth
中科院分区：
文献类型：
--
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
我们通过对147个黑色素瘤的外显子进行测序，描述了黑色素瘤的突变情况，黑色素瘤是死亡率最高的皮肤癌形式。与遮挡阳光的肢端、粘膜和葡萄膜黑色素瘤相比，暴露在阳光下的黑色素瘤有明显更多的紫外线样C>；T体细胞突变。在新发现的癌症基因中有PPP6C，它编码一种丝氨酸/苏氨酸磷酸酶，在12%的暴露于阳光下的黑色素瘤中，它含有聚集在活性部位的突变，仅在BRAF或NRAS突变的肿瘤中如此。值得注意的是，我们在9.2%的暴露在阳光下的黑色素瘤中发现了一种反复的紫外线特征，即RAC1中的一种激活突变。这种激活突变在我们的阳光照射黑色素瘤队列中仅次于BRAF和NRAS，在高度保守的Switch I结构域中将Pro29改变为丝氨酸(RAC1P29S)。RAC1P29S的晶体结构以及生化和功能研究表明，这种改变释放了保守的Pro带来的构象约束，导致蛋白质与下游效应物的结合增加，并促进了黑素细胞的增殖和迁移。这些发现增加了药物抑制RAC1信号的下游效应可能对治疗有益的可能性。
We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.
登录
查看更多内容
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.3
作者：
Douglas, Pauline;Zhong, Jianing;Lees-Miller, Susan P.
通讯作者：
Lees-Miller, Susan P.
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：
4.3
作者：
Halaban R;Zhang W;Bacchiocchi A;Cheng E;Parisi F;Ariyan S;Krauthammer M;McCusker JP;Kluger Y;Sznol M
通讯作者：
Sznol M
影响因子：
4.3
作者：
Bauer, Juergen;Buettner, Petra;Bastian, Boris C.
通讯作者：
Bastian, Boris C.