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

Jeremy Setton, Kevin Hadi, Zi-Ning Choo, Katherine S. Kuchin, Huasong Tian, Arnaud Cruz Paula, Joel Rosiene, Pier Selenica, Julie 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 () and Marcin Imieliński ()
Additional contact information
Jeremy Setton: Memorial Sloan Kettering Cancer Center
Kevin Hadi: Weill Cornell Medicine
Zi-Ning Choo: Weill Cornell Medicine
Katherine S. Kuchin: Weill Cornell Medicine
Huasong Tian: Weill Cornell Medicine
Arnaud Cruz Paula: Memorial Sloan Kettering Cancer Center
Joel Rosiene: Weill Cornell Medicine
Pier Selenica: Memorial Sloan Kettering Cancer Center
Julie Behr: Weill Cornell Medicine
Xiaotong Yao: Weill Cornell Medicine
Aditya Deshpande: Weill Cornell Medicine
Michael Sigouros: Weill Cornell Medicine
Jyothi Manohar: Weill Cornell Medicine
Jones T. Nauseef: New York Genome Center
Juan-Miguel Mosquera: Weill Cornell Medicine
Olivier Elemento: Weill Cornell Medicine
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Nadeem Riaz: Memorial Sloan Kettering Cancer Center
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Center
Simon N. Powell: Memorial Sloan Kettering Cancer Center
Marcin Imieliński: Weill Cornell Medicine

Nature, 2023, vol. 621, issue 7977, 129-137

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06461-2

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