Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers.

TitleLong-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers.
Publication TypeJournal Article
Year of Publication2023
AuthorsSetton J, Hadi K, Choo Z-N, Kuchin KS, Tian H, Paula ADa Cruz, Rosiene J, Selenica P, Behr J, Yao X, Deshpande A, Sigouros M, Manohar J, Nauseef JT, Mosquera J-M, Elemento O, Weigelt B, Riaz N, Reis-Filho JS, Powell SN, Imielinski M
Date Published2023 Sep
KeywordsBRCA1 Protein, BRCA2 Protein, Chromosome Aberrations, Chromosome Inversion, Cytogenetic Analysis, DNA Repair, Homologous Recombination, Humans, Neoplasms, Translocation, Genetic

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.

Alternate JournalNature
PubMed ID37587346
PubMed Central IDPMC10482687
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
P50 CA247749 / CA / NCI NIH HHS / United States
Related Faculty: 
Juan Miguel Mosquera, M.D.

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