同源重组不全（HR）缺陷与DNA重排和细胞遗传异常1相关。矛盾的是，仅对HR缺陷癌症特异关联的DNA重排类型对染色体结构几乎没有影响2。在这里，为了解决这个明显的矛盾，我们结合了数千个肿瘤的短读全基因组测序（WGS）和46个BRCA1或BRCA2突变乳腺癌的深度连接读WGS的基因组图分析。这些数据揭示了一类特异的HR缺陷丰度富集的重排，称为互为配对。连接读WGS显示具有相同重排方向的互为配对导致两种截然不同的染色体结果，只能通过长分子数据区分。其中一个（cis）结果对应于将一个小段复制并粘贴到一个远离位置，第二个（trans）结果是准平衡易位或多兆碱基倒位，并且在每个连接处都有大量（10 kb）的重复。我们提出了一种HR独立的复制重启修复机制，以解释互为配对结果的完整谱。连接读WGS还确定了单链缺口一致性是人类癌症中特异于BRCA2缺陷的修复途径。将这些特征集成到分类器中可以改善BRCA1和BRCA2缺陷基因组之间的区分。总之，我们的数据显示，HR缺陷细胞中特异于BRCA1或BRCA2缺陷的重排类是细胞遗传异常的来源。©2023.作者。

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.© 2023. The Author(s).