Decoding the BRCA2 reversion principles underlying PARP inhibitor resistance.

BRCA2 reversion mutations restoring homologous recombination function — sequence context-dependent and domain architecture-dependent

Using isogenic cell systems and CRISPR editing, this study defines the principles governing BRCA2 reversion mutations underlying PARP inhibitor (PARPi) resistance. Local sequence context dictates the spectrum of reversion events, while domain architecture determines which events confer PARPi resistance. Two reversion routes are characterized: DNA-level reading-frame restoration and transcript-level rescue via alternative splicing. Novel exon 11 reversion mechanisms are identified, including large genomic deletions and recurrent splice isoforms. These findings define a predictive code for BRCA2 reversion and PARPi resistance.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Predicting which reversion mutations are possible for each BRCA2 variant is a major advance for the clinical management of PARPi-treated germline BRCA2 carriers. This predictive code could enable prospective identification of patients at high risk of acquired resistance, development of targeted ctDNA surveillance for predicted reversions, and inform therapeutic sequencing. Preprint — to be confirmed after peer review.

Clinical impact : 3/3 · Evidence strength : 2/3 · Novelty : 2/2 · Sample size : 0/1 · Journal quality : 0/1 · Preprint penalty : -1 → Total : 6/10