title: 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=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=0.034, 0.027). TP53 expression differed between groups (P<0.0001), 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 (P<0.001). 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.
authors.affiliation: Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, Vancouver, BC, Canada. jessica.mcalpine@vch.ca
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.forename: Henry
authors.initials: H
authors.lastname: Porter
authors.forename: Martin
authors.initials: M
authors.lastname: Köbel
authors.forename: Brad H
authors.initials: BH
authors.lastname: Nelson
authors.forename: Leah M
authors.initials: LM
authors.lastname: Prentice
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Katy
authors.initials: K
authors.lastname: Milne
authors.forename: Jiarui
authors.initials: J
authors.lastname: Ding
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
mesh_terms: D000368:Aged; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011446:Prospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004273:DNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases