Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

Abstract

BackgroundSubclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas.MethodsA consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry.ResultsEighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1.ConclusionHigh grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

“…13 Reasons for this discrepancy are likely related to the methodologic approach used, as well as with the lack of information on CDH1 LOH analysis in previous reports. In other cancer-associated syndromes, the frequency of 2nd-hit mechanisms identified is similar to that herein described as 60% of hereditary nonpolyposis colorectal cancer tumors displaying hMLH1 hypermethylation and LOH, 17,18 75% of familial ovarian cancer displaying BRCA2 LOH, 19 and 83% of familial adenomatous polyposis desmoid tumors displaying APC somatic mutations and deletions. 20 To have a full picture of how CDH1 are inactivated in this invasive and spreading disease, we have analyzed a series of primary tumors and metastasis as well as several primary tumor foci and metastatic lesions from the same patient, whenever possible.…”

“…15,16 Data from 27 tumors arising in 27 patients from the 13 HDGC families studied so far still indicate CDH1 promoter hypermethylation as the most common 2nd-hit mechanism of inactivation. 10,11,14 In contrast with studies on the 2nd-hit inactivation mechanism of genes causing other neoplastic syndromes, [17][18][19][20] somatic genetic alterations (mutations and loss of heterozygosity [LOH]) of CDH1 were uncommonly found. 10 -12,14 As a consequence, CDH1 promoter hypermethylation has been suggested as the basis for development of early detection tools as well as for chemoprophylaxis in unaffected CDH1 mutation carriers.…”

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

“…Forty-nine of the cases in this series were the subject of a previous report on characterization of BRCA1 and BRCA2 abnormalities in ovarian carcinoma (recruitment beginning 2004). 26 This previous study did not include analysis of clinical features, including patient outcomes. Recruitment continued until the spring of 2009 with the goal of minimum 2 years follow-up in all individuals.…”

“…[18][19][20][21][22][23][24] Germline mutations in BRCA1 and BRCA2 are present in B18% of ovarian cancer patients with high-grade serous carcinoma. [25][26][27] When combined with BRCA deficiencies that result from somatic mutations or epigenetic silencing, it appears that up to half of all high-grade serous ovarian cancers (hereditary and sporadic) have BRCA dysfunction. 15,[26][27][28][29][30] BRCA1 and BRCA2 genes encode functionally related proteins that play a critical role in repair of DNA double-strand breaks.…”

“…[25][26][27] When combined with BRCA deficiencies that result from somatic mutations or epigenetic silencing, it appears that up to half of all high-grade serous ovarian cancers (hereditary and sporadic) have BRCA dysfunction. 15,[26][27][28][29][30] BRCA1 and BRCA2 genes encode functionally related proteins that play a critical role in repair of DNA double-strand breaks. [31][32][33] Loss of BRCA function results in development of chromosomal instability.…”