Exploring the differences between BRCA mutated and HRwild-type high grade serous ovarian cancer: A multiomic analysis.

Objective: The purpose of this study was to evaluate the transcriptomic profile of BRCA1 mutant (BRCA1mut) and BRCA2 mutant (BRCA2mut) HGSOC compared to homologous recombination wild-type (HRwt) tumors utilizing the CARIS database.

Methods: Next-generation and Whole Transcriptome Sequencing (WTS; Caris Life Sciences, Phoenix, AZ) was performed on a total of 2745 HGSOC tumor samples. BRCA mutations were defined as variants resulting in loss-of-function of the protein and HRwt was defined as samples wildtype for aberrations in both BRCA1 and BRCA2, as well as for 28 other HR genes. HRwt group was further classified into HRwt/LOH-low (<16 %) and HRwt/LOH-high (≥16 %). Genomic analysis consists of mutation analysis and measurements of TMB and MSI. Transcriptomic analysis included identification of Differentially expressed genes (DEGs), GSEA and immune deconvolution.

Results: We identified 519 (19 %) BRCA1-mut, 302 (11 %) BRCA2-mut, and 739 (27 %) HRwt/LOH high and 1181 (43 %) HRwt/LOH low HGSOC. TP53 was the most commonly mutated gene in all groups. Mutations in PIK3CA were most common in HRwt/LOH-low compared to BRCA1-mut and BRCA2-mut HGSOC. TMB-H was highest in BRCA2-mut compared to BRCA1-mut, HRwt/LOH high and HRwt/LOH low tumors. In contrast, higher NKT cell infiltration, higher T cell inflamed and IFNγ scores, and higher PDL1 expression were observed in BRCA1-mut tumors.

Conclusion: Our findings emphasize the differential immune profiles based on BRCA1 and BRCA2 mutations and suggest potential therapeutic targets, including treatment strategies that incorporate immunotherapy and target specific genomic alterations.