Multigene germline and somatic testing for epithelial ovarian cancer in China

Abstract

This study investigated BRCA1/2 and homologous recombination repair (HR) pathway gene variants in Chinese epithelial ovarian cancer (EOC) patients. Germline and somatic variants in 21 HR-related genes were analyzed in 229 patients using a 21-gene ovarian panel and in 141 patients using a 508-gene pan-cancer panel. BRCA1, BRCA2, and HR-related gene mutation rates were 17.9%, 3.5%, and 23.1%, respectively, with TP53 as the most frequent somatic mutation (66.4%). Combined germline and somatic BRCA1/2 mutation rates rose to 23.6 and 6.1%. Survival analysis (n = 200) demonstrated longer overall survival (OS) in patients carrying BRCA1/2 or HR mutations. Notably, strategies including likely pathogenic (LP) and variants of uncertain significance (VUS) showed improved OS, especially in BRCA2 and BRCA1/2 somatic carriers. These findings suggest that integrating germline, somatic, and VUS data enhances survival prediction and guides treatment decisions in Chinese EOC patients.

Fig. 1. Deleterious variant type and frequency in EOC patients.

A Distribution of pathogenicity of germline mutation carriers. B Distribution of genes with germline deleterious mutations. C Distribution of mutation types of BRCA1 and BRCA2. D Distribution of pathogenicity of somatic mutation carriers. E Distribution of genes with deleterious somatic mutations. F Distribution of mutation types of TP53 and BRCA1. G proportion of germline, somatic, and germline + somatic mutation carriers in genes, HRo refers to HR-related genes other than BRCA1 and BRCA2.

Fig. 2. OS and PFS by mutation status.

Five-year Kaplan‒Meier curve for OS and PFS in EOC patients stratified by A, D germline + somatic mutation carriers of HR genes under LP+ strategy, B, E germline + somatic mutation carriers of HR genes under VUS+ strategy, and C, F germline + somatic mutation carriers of BRCA1/2 genes under VUS+ strategy. The p values were calculated with the log-rank test. WT wild-type (including no variants, benign and likely benign variants), LP+ likely pathogenic and pathogenic variants. VUS+, LP+, and VUS variants. Tier II+, class I and II somatic variants, Tier III+, class I, II, and III somatic variants.

Fig. 3. Forest plot of multivariate Cox regression with BRCA1, BRCA2, and other HR related gene mutation status.

Forest plot of hazard ratios for A OS and B PFS associated with LP+ (blue) and VUS+ (red) mutations across individual genes and gene sets. The Cox model was adjusted for age at diagnosis, FIGO stage, and histological subtype. Non-carriers served as the reference group. Hazard ratios are shown with 95% confidence intervals. CI confidence interval, *** p < 0.001; * 0.01 < p < 0.05; †p < 0.1.