Citations 1
Landscape of reversion alterations in homologous recombination genes reveals evolutionary constraints
Decker, Brennan, Sisoudiya, Saumya D. , Thornton, James, Cui, Chenming, Solieva, Shahlo , Shi, Tao, Guintini, Fabio, Fleischmann, Zoe, Hartman, Mark, Bailey, Shannon T., Leibowitz, Jeffrey , Sokol, Ethan S, Schrock, Alexa B. , Couch, Fergus J, Reiss, Kim A, Domchek, Susan M, Sivakumar, Smruthy, Decker, Brennan , Cui, Chenming , Harada, Taku, Madison, Russell W. , Datta, Arindam , Fleischmann, Zoe , Frampton, Garrett M. , Couch, Fergus J. , Reiss, Kim A. , Domchek, Susan M. , Bowman, Gregory R. , Greenberg, Roger A. , Nathanson, Katherine L.
No container title available | May 22, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
ABSTRACT Reversion mutations (REVs) restore homologous recombination repair (HRR) and confer resistance to PARP inhibitors (PARPi) in HR-deficient cancers. Yet, their prevalence, mechanisms, and biological constraints remain undefined. We analyzed genomic profiling of 609,464 tissue and liquid biopsy samples across multiple cancer types to delineate the pan-cancer landscape of REVs. REVs were identified in eight HRR genes, most frequently BRCA2 and BRCA1 and notably never in ATM or CHEK2 . REVs exclusively impacted truncating pathogenic variants, predominantly through large in-frame and exon-level deletions, associated with repetitive sequences. Conserved functional domains are relatively depleted of REVs. Structural modeling and functional studies support that exon-level deletions preserve critical domain architecture and confer PARPi resistance. The study establishes HRR reversion as a structurally permissive, yet evolutionarily constrained, resistance mechanism with implications on response, monitoring, and therapeutic strategy. One Sentence Summary Homologous recombination reversion evolves through structurally tolerated, microhomology-driven alterations that restore DNA repair under therapeutic selection across cancers.