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

   


Authors: Setton, J.; Hadi, K.; Choo, Z. N.; Kuchin, K. S.; Tian, H.; Da Cruz Paula, A.; Rosiene, J.; Selenica, P.; Behr, J.; Yao, X.; Deshpande, A.; Sigouros, M.; Manohar, J.; Nauseef, J. T.; Mosquera, J. M.; Elemento, O.; Weigelt, B.; Riaz, N.; Reis-Filho, J. S.; Powell, S. N.; Imieliński, M.
Article Title: Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers
Abstract: 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).
Keywords: controlled study; gene translocation; genetics; pathogenesis; sensitivity and specificity; dna replication; neoplasm; neoplasms; chromosome; homologous recombination; dna repair; breast cancer; cohort analysis; cytogenetics; brca1 protein; brca2 protein; tumor suppressor gene; dna; gene rearrangement; molecular analysis; gene duplication; translocation, genetic; genome; cancer classification; brca1 protein, human; scar; receiver operating characteristic; recombination; gene replication; translocation; cicatrix; diagnostic test accuracy study; chromosome inversion; brca2 protein, human; cancer; humans; human; article; whole genome sequencing
Journal Title: Nature
Volume: 621
Issue: 7977
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2023-09-07
Start Page: 129
End Page: 137
Language: English
DOI: 10.1038/s41586-023-06461-2
PUBMED: 37587346
PROVIDER: scopus
PMCID: PMC10482687
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85168102478&doi=10.1038%2fs41586-023-06461-2&partnerID=40&md5=4ac8e4999da9532ec75a46a84f049e30
Notes: Article -- Source: Scopus
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MSK Authors
  1. Simon Nicholas Powell
    331 Powell
  2. Nadeem Riaz
    417 Riaz
  3. Jeremy Setton
    93 Setton
  4. Britta Weigelt
    633 Weigelt
  5. Jorge Sergio Reis-Filho
    639 Reis-Filho
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