Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.
Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.
复制标题
DOI：
10.1038/s41588-020-0708-0
复制
发表时间：
2020-11
期刊：
影响因子：
30.8
通讯作者：
Andrew Futreal P
中科院分区：
文献类型：
--
作者：
Akdemir KC;Le VT;Kim JM;Killcoyne S;King DA;Lin YP;Tian Y;Inoue A;Amin SB;Robinson FS;Nimmakayalu M;Herrera RE;Lynn EJ;Chan K;Seth S;Klimczak LJ;Gerstung M;Gordenin DA;O'Brien J;Li L;Deribe YL;Verhaak RG;Campbell PJ;Fitzgerald R;Morrison AJ;Dixon JR;Andrew Futreal P
驱动基因的体细胞突变可能最终导致癌症的发展。因此，了解体细胞突变如何在癌症基因组中积累以及产生体细胞突变的潜在因素对于开发新的治疗策略至关重要。为了了解空间基因组组织和特定突变过程之间的相互作用，我们研究了来自42种不同人类癌症类型的3，000个肿瘤-正常对全基因组数据集。我们的分析表明，癌症基因组中体细胞突变负荷的变化与拓扑关联域（topologically associated domain，简称domain）边界共定位。域边界构成了一个更好的代理，以跟踪突变的负载变化比复制定时测量。我们发现，不同的突变过程导致不同的体细胞突变分布，其中某些过程产生突变的活性结构域和其他非活性结构域。总的来说，三维基因组组织和活跃的突变过程之间的相互作用对人类癌症中观察到的大规模突变率变化具有重大影响。
Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically associating domain (TAD) boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains and others in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancers.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
3.5
作者：
Dekker J;Heard E
通讯作者：
Heard E
影响因子：
12.3
作者：
Akdemir KC;Chin L
通讯作者：
Chin L
影响因子：
64.5
作者：
Haradhvala NJ;Polak P;Stojanov P;Covington KR;Shinbrot E;Hess JM;Rheinbay E;Kim J;Maruvka YE;Braunstein LZ;Kamburov A;Hanawalt PC;Wheeler DA;Koren A;Lawrence MS;Getz G
通讯作者：
Getz G
影响因子：
30.8
作者：
Chan K;Roberts SA;Klimczak LJ;Sterling JF;Saini N;Malc EP;Kim J;Kwiatkowski DJ;Fargo DC;Mieczkowski PA;Getz G;Gordenin DA
通讯作者：
Gordenin DA