Backup DNA Repair Causes Large Rearrangements in BRCA1/2-Deficient Tumors

Many cancers exhibit deficiencies in homologous recombination (HR) due to mutations in genes that encode critical mediators of HR, such as BRCA1 and BRCA2. In the absence of high-fidelity, HR-mediated repair, cancer cells rely on mutation-prone backup mechanisms to repair DNA double-strand breaks and display characteristic patterns of genetic alterations. Despite the large-scale cytogenetic aberrations observed in HR-deficient tumors, the DNA rearrangements that have been associated with BRCA1-deficient (BRCA1d) and BRCA2-deficient (BRCA2d) tumors are alterations that minimally affect chromosomal structure. To understand this paradox and examine how HR deficiency leads to cytogenetic changes, Setton, Hadi, Choo, and colleagues analyzed short-read whole-genome sequencing (WGS) data from 979 primary breast, ovarian, prostate, and pancreatic tumors and focused on near-reciprocal structural variants (SV), which are rearrangements that involve a pair of widely separated DNA junctions with break ends that produce copy-number loss or gain of the segment of the genome immediately adjacent to the break. Comparison of near-reciprocal SVs in BRCA1d, BRCA2d, or HR-proficient tumors revealed a class of SVs termed reciprocal pairs that could be divided into three subtypes: reciprocal duplications enriched in BRCA1d tumors, reciprocal deletions enriched in BRCA2d tumors, and reciprocal deletion duplications enriched in BRCA1d and BRCA2d tumors. Linked-read WGS analysis of 46 BRCA1d or BRCA2d breast cancers determined that reciprocal pairs with identical rearrangement orientations gave rise to one of two chromosomal outcomes, leading to either the copying and pasting of a small segment to a distant site or a large-scale rearrangement via a balanced translocation or inversion, and these distinct outcomes pointed to an HR-independent, replication-restart DNA repair mechanism. Moreover, long-molecule analysis uncovered genomic scars consistent with a special type of single-strand annealing with mismatch correction as a backup repair pathway in BRCA2d tumors. A pan-cancer HR deficiency classifier based on these SV features distinguished between BRCA1d and BRCA2d tumors. In summary, these findings describe reciprocal pairs as a class of SVs that can lead to large-scale rearrangements associated with BRCA1 or BRCA2 deficiency in HR-deficient tumors.

Setton J, Hadi K, Choo ZN, Kuchin KS, Tian H, Da Cruz Paula A, et al. Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers. Nature 2023 Aug 16 [Epub ahead of print].

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