癌症基因組中的體細胞突變分布隨三維染色質結構而變化
作者：
小柯機器人發布時間：2020/10/10 13:48:49
美國德克薩斯大學MD安德森癌症中心P. Andrew Futreal等研究人員合作發現，癌症基因組中的體細胞突變分布隨三維染色質結構而變化。該研究於2020年10月5日在線發表於國際一流學術期刊《自然—遺傳學》。
為了解空間基因組組織與特定突變過程之間的相互作用，研究人員分析了來自42種不同人類癌症類型的3,000個腫瘤-正常對全基因組數據集。分析表明，癌症基因組中體細胞突變負荷的變化與拓撲相關域邊界共同定位。與複製時序測量相比，域邊界構成了更好的指標來跟蹤突變負載變化。研究人員表明不同的突變過程導致不同的體細胞突變分布，其中某些過程在活性域中生成突變，而其他過程在非活性域中生成突變。
總體而言，三維基因組組織與主動突變過程之間的相互作用對人類癌症中觀察到的大規模突變率變異具有重大影響。
據悉，驅動基因的體細胞突變可能最終導致癌症的發展。因此，了解體細胞突變如何在癌症基因組中積累以及產生體細胞突變的潛在因素對於開發新的治療策略至關重要。
附：英文原文
Title: Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure
Author: Kadir C. Akdemir, Victoria T. Le, Justin M. Kim, Sarah Killcoyne, Devin A. King, Ya-Ping Lin, Yanyan Tian, Akira Inoue, Samirkumar B. Amin, Frederick S. Robinson, Manjunath Nimmakayalu, Rafael E. Herrera, Erica J. Lynn, Kin Chan, Sahil Seth, Leszek J. Klimczak, Moritz Gerstung, Dmitry A. Gordenin, John OBrien, Lei Li, Yonathan Lissanu Deribe, Roel G. Verhaak, Peter J. Campbell, Rebecca Fitzgerald, Ashby J. Morrison, Jesse R. Dixon, P. Andrew Futreal
Issue&Volume: 2020-10-05
Abstract: 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 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 generate mutations 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. Somatic mutational loads in cancer genomes change with chromatin domain boundaries. Different mutational processes lead to distinct somatic mutation distributions in active versus inactive domains, including during tumor evolution.
DOI: 10.1038/s41588-020-0708-0
Source: https://www.nature.com/articles/s41588-020-0708-0