生物
基因组
遗传学
同源重组
非等位同源重组
DNA修复
DNA
节段重复
染色体反转
计算生物学
基因
染色体
核型
重组
遗传重组
基因家族
作者
Jeremy Setton,Kevin Hadi,Zi-Ning Choo,Katerina Kuchin,Huasong Tian,Arnaud Da Cruz Paula,Joel Rosiene,Pier Selenica,Julie M. Behr,Xiaotong Yao,Aditya Deshpande,Michael Sigouros,Jyothi Manohar,Jones T. Nauseef,Juan Miguel Mosquera,Olivier Elemento,Britta Weigelt,Nadeem Riaz,Jorge S. Reis‐Filho,Simon N. Powell,Marcin Imieliński
出处
期刊:Nature
[Springer Nature]
日期:2023-08-16
卷期号:621 (7977): 129-137
被引量:4
标识
DOI:10.1038/s41586-023-06461-2
摘要
Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations1. Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure2. Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers. These data revealed a distinct class of HR-deficiency-enriched rearrangements called reciprocal pairs. Linked-read WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long-molecule data. Whereas one (cis) outcome corresponded to the copying and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10 kb) duplications at each junction. We propose an HR-independent replication-restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. Linked-read WGS also identified single-strand annealing as a repair pathway that is specific to BRCA2 deficiency in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- and BRCA2-deficient genomes. In conclusion, our data reveal classes of rearrangements that are specific to BRCA1 or BRCA2 deficiency as a source of cytogenetic aberrations in HR-deficient cells.
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