Functional Homologous Recombination (HR) Screening Shows the Majority of -Mutant Breast and Ovarian Cancer Cell Lines Are HR-Proficient.

Tumors with a pathogenic mutation are homologous recombination (HR)-deficient (HRD) and consequently sensitive to platinum-based chemotherapy and Poly-[ADP-Ribose]-Polymerase inhibitors (PARPi). We hypothesized that functional HR status better reflects real-time HR status than mutation status. Therefore, we determined the functional HR status of 53 breast cancer (BC) and 38 ovarian cancer (OC) cell lines by measuring the formation of RAD51 foci after irradiation. Discrepancies between functional HR and mutation status were investigated using exome sequencing, methylation and gene expression data from 50 HR-related genes. A pathogenic mutation was found in 10/53 (18.9%) of BC and 7/38 (18.4%) of OC cell lines. Among -mutant cell lines, 14/17 (82.4%) were HR-proficient (HRP), while 1/74 (1.4%) wild-type cell lines was HRD. For most (80%) cell lines, we explained the discrepancy between functional HR and mutation status. Importantly, 12/14 (85.7%) -mutant HRP cell lines were explained by mechanisms directly acting on BRCA1/2. Finally, functional HR status was strongly associated with COSMIC single base substitution signature 3, but not mutation status. Thus, the majority of -mutant cell lines do not represent a suitable model for HRD. Moreover, exclusively determining mutation status may not suffice for platinum-based chemotherapy or PARPi patient selection.