Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.
Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.
复制标题
DOI：
10.1126/science.aaa6806
复制
发表时间：
2015-05-22
期刊：
影响因子：
--
通讯作者：
Campbell PJ
中科院分区：
文献类型：
--
作者：
Martincorena I;Roshan A;Gerstung M;Ellis P;Van Loo P;McLaren S;Wedge DC;Fullam A;Alexandrov LB;Tubio JM;Stebbings L;Menzies A;Widaa S;Stratton MR;Jones PH;Campbell PJ
体细胞突变是如何在正常细胞中积累的，这是理解癌症发展的核心，但人们对此知之甚少。我们对正常皮肤的小样本(0.8-4.7mm2)的74个癌症基因进行了超深测序。在来自四个人的234份暴露在阳光下的眼皮活检中，体细胞突变的负担平均为2-6个突变/兆基/细胞，类似于许多癌症，并表现出紫外线暴露的特征特征。值得注意的是，即使在生理正常的皮肤中，多种癌症基因也处于强阳性选择之下，包括大多数皮肤鳞状细胞癌的关键驱动因素。在密度约为140/cm2的正常皮肤细胞中，18-32%的正常皮肤细胞中发现了阳性选择的“DIVER”突变。我们观察到个体间驱动环境的可变性，以及跨基因克隆扩展的大小的可变性。因此，老化、暴露在阳光下的皮肤是数千个进化克隆人的拼凑而成的，超过四分之一的细胞携带致癌突变，同时保持表皮的生理功能。
How somatic mutations accumulate in normal cells is central to understanding cancer development, but is poorly understood. We performed ultra-deep sequencing of 74 cancer genes in small (0.8-4.7mm2) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged 2-6 mutations/megabase/cell, similar to many cancers, and exhibited characteristic signatures of ultraviolet light exposure. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected ‘driver’ mutations were found in 18-32% of normal skin cells at a density of ~140/cm2. We observed variability in the driver landscape among individuals and variability in sizes of clonal expansions across genes. Thus, aged, sun-exposed skin is a patchwork of thousands of evolving clones, with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis.
登录
查看更多内容
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
14.9
作者：
Guo J;Hanawalt PC;Spivak G
通讯作者：
Spivak G
影响因子：
8.8
作者：
McKerrell T;Park N;Moreno T;Grove CS;Ponstingl H;Stephens J;Understanding Society Scientific Group;Crawley C;Craig J;Scott MA;Hodkinson C;Baxter J;Rad R;Forsyth DR;Quail MA;Zeggini E;Ouwehand W;Varela I;Vassiliou GS
通讯作者：
Vassiliou GS
DOI：
10.1073/pnas.91.1.360
发表时间：
1994-01-04
影响因子：
11.1
作者：
NAKAZAWA, H;ENGLISH, D;YAMASAKI, H
通讯作者：
YAMASAKI, H
影响因子：
8.8
作者：
Harvey, I;Frankel, S;NolanFarrell, M
通讯作者：
NolanFarrell, M