Heterozygous BRCA1 SNPs in the Central Functional Region are Associated With Increased Sensitivity to PARP Inhibition...

Poly (ADP-ribose) polymerase (PARP) inhibitors demonstrate efficacy in breast cancer patients harboring pathogenic BRCA1/2 mutations. However, certain BRCA1 single nucleotide polymorphisms may alter protein function without complete loss of activity. This study investigates whether specific heterozygous BRCA1 single nucleotide polymorphisms within the central functional region of BRCA1 affect cellular sensitivity to PARP inhibition and explores the underlying transcriptomic mechanisms.

Two breast cancer cell lines were employed: CAMA-1, carrying heterozygous BRCA1 SNPs (rs799917, rs16941, rs16942, and rs1799966), and T47D, harboring wild-type BRCA1. Cell viability following olaparib treatment was assessed using the MTT assay at multiple concentrations and time points. Whole-transcriptome sequencing was subsequently performed, followed by functional enrichment and pathway analyses to characterize differential gene expression between the 2 cell lines under PARP inhibition stress.

CAMA-1 cells exhibited significantly enhanced olaparib sensitivity compared to T47D cells, with viability reduced to 45% versus 75% at 50 μM after 72 hours (P < .001). Transcriptome analysis identified 6978 differentially expressed genes, with significant enrichment in pathways related to DNA binding, transcriptional regulation, and cellular degradation, a pattern consistent with a model of conditional haploinsufficiency, though this interpretation requires direct experimental validation.

Heterozygous BRCA1 SNPs in the central functional region of BRCA1 are associated with increased PARP inhibitor sensitivity in the absence of pathogenic mutations. These preliminary findings identify these variants as candidates warranting further investigation as potential predictive biomarkers for PARP inhibitor response.