Germline BRCA1/2-associated multi-omic landscape in High Grade Serous Ovarian Cancer (HGSOC): insights from the PowerOMICS study

Germline BRCA1/2 mutations are prevalent in high-grade serous ovarian carcinoma (HGSOC) and influence tumor biology and treatment response. Although the genomic consequences of homologous recombination repair (HR) deficiency are well established, the integrated multi-omic landscape characterizing tumors carrying these germline variants remains incompletely characterized. In the novel prospective Polish PowerOMICS HGSOC cohort (n = 76), we integrated tumor RNA-seq, smallRNA-seq, and methylome data using unsupervised Multi-Omics Factor Analysis (MOFA2), with germline and somatic HR status. Factors and stratified patient groups were tested for clinical and molecular associations by logistic regression, Cox modelling, gene set enrichment and signature scoring. Germline pathogenic BRCA1/2 variants were detected in 22.4% of PowerOMICS HGSOC patients. Sixteen MOFA2 factors explained 54.21%, 41.01% and 32.80% of RNA-seq, smallRNA-seq and methylome variance. Factor 13 was independently associated with g BRCA1/2 (R = 0.3708, P = 0.001; multivariable OR = 6.43, P = 0.00595). It integrated matrisome reorganization (R = 0.45, P = 2.2 × 10 –4 ), E2F/G2-M transcriptional programs (ORA P = 8.91 × 10 –16 and P = 2.13 × 10 –11 ) and elevated POLQ expression alongside enrichment of the HR gene set (GSEA NES = 2.18, FDR < 0.0001). Factor 6 associated with somatic HR and BRCA1/2 copy number alterations (R = 0.370, P = 0.001), with BRCA1 promoter hypermethylation as an independent epigenetic contributor ( P = 0.0116). Factor 3 captured immune microenvironmental remodeling (ImmunoScore R = 0.735, P = 7.1 × 10 –12 ), while factor 8 captured a DNA-replication signature (R = 0.43, P = 4.6 × 10 –4 ), both linked to somatic HR alterations. In a multivariable model adjusted for gBRCA1/2 status, factors 14 (HR = 2.63, 95% CI 1.33–5.21) and 16 (HR = 0.61, 95% CI 0.40–0.93) were significantly associated with overall survival after correction for multiple testing. Factor 13 association was reproduced, with a smaller effect size, in an independent TCGA-OV cohort ( n = 415; Cliff's d = 0.27; P = 0.002). Multi-omic factor analysis identified regulatory programs associated with germline and somatic HR deficiency in HGSOC. Germline BRCA1/2 status was related to a coordinated program characterized by extracellular matrix remodeling, DNA repair, and cell-cycle related transcriptional programs and elevated POLQ expression. Matrisome reorganization emerged as a prominent feature associated with the germline BRCA1/2 multi-omic tumor profile. Together, these findings advance understanding of germline BRCA1/2 -related HGSOC as a coordinated multi-layer regulatory state.