Two decades of PARP inhibitor synthetic lethality in cancer.

BRCA–PARP synthetic lethality: homologous recombination deficiency + PARP inhibition → selective killing of BRCA-deficient tumor cells

Twenty years after the landmark discovery of BRCA–PARP synthetic lethality, this review by the field's pioneers traces the clinical translation arc from bench to bedside. PARP inhibitors are now approved for germline BRCA1/2-mutant breast, ovarian, prostate, and pancreatic cancers, transforming germline BRCA testing from a risk-stratification tool into a companion diagnostic biomarker that directly guides therapy. The review also traces how the synthetic lethality concept has spurred the search for other exploitable tumor-specific vulnerabilities beyond BRCA.

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

This Nature review by the founding authors is essential reading for any clinician involved in cancer genetics. It underscores the paradigm shift in germline BRCA testing: from risk assessment in unaffected individuals to a companion diagnostic biomarker directly guiding targeted therapy in cancer patients. The ongoing shift toward mainstreaming — BRCA testing ordered by oncologists, not only geneticists — is a structural trend that clinical genetics practice must accommodate.

Clinical impact : 3/3 · Evidence strength : 2/3 · Novelty : 1/2 · Sample size : 1/1 · Journal quality : 1/1 → Total : 8/10