BRCA1and BRCA2mutations correlate with TP53abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

We characterized BRCA1and BRCA2status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1and BRCA2 mutations. Histopathology, germline and somatic BRCA1or BRCA2 mutations, BRCA1methylation, and BRCA1and BRCA2mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2mutations (20% BRCA1and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1(group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1and BRCA2mRNA expression levels correlated with designated group (P=0.0008). Among high-grade serous carcinomas, there were no differences between groups 1–3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1or BRCA2mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P=0.034, 0.027). TP53expression differed between groups (P<0.0001), with abnormal TP53expression in 49/50 tumors from groups 1 and 2. Wild-type TP53expression was associated with worse outcome in high-grade serous (P<0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1or BRCA2, compared with tumors lacking BRCA abnormalities.