Landscape of reversion alterations in homologous recombination genes reveals evolutionary constraints

作者：Brennan Decker, Saumya D. Sisoudiya, James Thornton, Chenming Cui, Taku Harada, Shahlo Solieva, Russell W. Madison, Arindam Datta, Tao Shi, Fabio Guintini, Zoe Fleischmann, Mark Hartman, Shannon T. Bailey, Jeffrey Leibowitz, Ethan S Sokol, Alexa B. Schrock, Garrett M. Frampton, Fergus J Couch, Kim A Reiss, Susan M Domchek, Gregory R. Bowman, Roger A. Greenberg, Smruthy Sivakumar, Katherine L. Nathanson · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.05.19.726319 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、BRCA gene mutations in cancer

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.