Morphologic Correlations With Homologous Recombination Deficiency in High-grade Serous Carcinomas.

Abstract

High-grade serous carcinomas (HGSCs) with homologous recombination deficiency (HRD) respond favorably to platinum therapy and poly ADP ribose polymerase (PARP) inhibitors. Mutations in BRCA1 and BRCA2 commonly cause HRD and have been associated with Solid, pseudoEndometrioid, and Transitional-like (SET-like) histology. Mutations in other homologous recombination repair (HRR) genes as well as epigenetic changes can also result in HRD; however, morphologic correlates have not been well-explored in these cases. We hypothesized that HGSCs with HRD, regardless of the etiology, are associated with specific morphologic features. Forty-three cases of HGSC with genomic profiling, which included HRR gene mutation analysis and HRD score, were evaluated. The morphologic patterns, degree of nuclear atypia, necrosis, mitotic index, and tumor-infiltrating lymphocytes (TILs) were determined. The results showed that HRD-high status was significantly associated with the presence of BRCA1/2 mutation, SET-like morphology, geographic necrosis, and severe nuclear atypia. Additional HRR pathway genes with oncogenic mutations identified included ATM, BRIP1, BLM, FANCC, CDK12, CHEK2, RAD51C, and RAD51D. Almost one-third of HRD-high tumors did not have mutations in any HRR pathway genes identified. In conclusion, HGSC with HRD, regardless of BRCA1/2-status, was associated with SET-like morphology and more severe nuclear atypia. Identifying and reporting these patterns of tumor morphology can prompt genomic profiling with prognostic, therapeutic, and genetic counseling implications.