BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

Abstract

We characterized BRCA1 and BRCA2 status (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 BRCA1 or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1 or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA 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 BRCA2 mutations (20% BRCA1 and 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. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P ¼ 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 BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P ¼ 0.034, 0.027). TP53 expression differed between groups (Po0.0001), with abnormal TP53 expression in 49/50 tumors from groups 1 and 2. Wild-type TP53 expression was associated with worse outcome in high-grade serous (Po0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1 or BRCA2, compared with tumors lacking BRCA abnormalities.

Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease

“…It has been proposed that mutations in the TP53 tumor suppressor gene is one of earliest mutational events in HGS as nearly all cases harbor a somatic mutation in this gene as confirmed by a recent molecular genetic profiling of over 300 HGS samples by The Cancer Genome Atlas Research (TCGA) network [12, 13]. Furthermore, compromised homologous recombination due to loss of BRCA1 and BRCA2 function, by the inheritance of a germline pathogenic mutation in approximately 10-20% of HGS cases [12], or through somatic means by acquiring an intragenic mutation or epigenetic silencing [12, 14, 15], occurs in approximately one third of the HGS EOC cases. The prevalence of TP53 mutations and BRCA1 / BRCA2 deficiency likely leads to incompetent DNA repair which in turn contributes to chromosomal instability, resulting in severely aberrant karyotypes.…”

Outcomes of Incidental Fallopian Tube High-Grade Serous Carcinoma and Serous Tubal Intraepithelial Carcinoma in Women at Low Risk of Hereditary Breast and Ovarian Cancer

“…Although we excluded patients with a known or suspected germline BRCA1 or BRCA2 mutation at the time of surgery from this study, 17% or more of patients with HGSC will have such a mutation 22 and one patient in this series did eventually test positive for a BRCA1 mutation 3 years after her diagnosis with STIC. Therefore, others in our cohort may also carry a BRCA mutation.…”

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

“…Moreover, BRCA1-2 mutated tumors showed a significantly increased CD3 + and CD8 + TIL number anda significantly higher expression of PD-1 and PD-L1 compared with HR-proficient tumors. Therefore, BRCA1-2-mutated HGSOCs could represent a subset of tumors fit for treatment with immune checkpoint inhibitors alone or in combination with poly(adenosine diphosphate (ATP-ribose) polymerases (PARP) inhibitors (57)(58)(59). Moreover, Strickland et al (60) found that 3 out of 30 (10%) CCOCs exhibited microsatellite instability (MSI) and that CCOCs with MSI had a higher number of CD3 + TILs and higher number of PD1-positive TILs compared with both microsatellite stable (MSS) CCOCs Gadducci and Guerrieri: Immune Checkpoint Inhibitors in Gynecological Cancers (Review) 5957 The NCT02571725 trial will assess the side-effects and best dose of tremelimumab when given together with the PARP inhibitor olaparibin patients with recurrent platinumsensitive or platinum-resistant EOC, fallopian tube cancer (FTC) or primary peritoneal cancer (PPC) and germline BRCA1 or BRCA2 mutation.…”