Endometrial Cancer Risk in Women with Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study.
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ABSTRACT: Background
Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain, therefore we assessed this in a large Dutch nationwide cohort study.Methods
5,980 BRCA1/2 (3,788 BRCA1, 2,151 gBRCA2, 41 both BRCA1/BRCA2) and 8,451 non-BRCA1/2 mutation carriers were selected from the HEBON-cohort. Follow-up started at date of nationwide PALGA coverage (January 1, 1989) or at the age of 25 years (whichever came last), and ended at date of EC diagnosis, last follow-up or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared to: 1) general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were two-sided.Results
Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119,296 and 160,841 person-years, respectively (SIR = 2.83, 95% confidence interval (CI) = 2.18-3.65; and HR = 2.37, 95% CI = 1.53-3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61-4.72; HR = 2.91, 95% CI = 1.83-4.66), serous-like EC (SIR: 12.64, 95% CI = 7.62-20.96; HR = 10.48, 95% CI = 2.95-37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80-3.83; HR = 2.01, 95% CI = 1.18-3.45) and TP53-mutated EC (HR = 15.71, 95% CI = 4.62-53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01-2.87), and serous-like EC risks (SIR = 5.11, 95% CI = 1.92-13.63) were increased when compared to the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%).Conclusions
BRCA1/2 mutation carriers have a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.
SUBMITTER: de Jonge MM
PROVIDER: S-EPMC8418438 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pathogenic BRCA1/2 germline mutations confer high risks of breast and ovarian cancer to women of European ancestry. Characterization of BRCA1/2 mutations in other ethnic groups is also medically important. We comprehensively screened 68 Colombian breast/ovarian cancer families for small-range mutations, 221 families for large-genomic rearrangements, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. The risk of cancer among relatives of mutation carriers and the mutation penetrance were estimated by survival analysis. Identified BRCA2 mutations included 6310delGA and the recurrent 1991del4 mutations. A novel large BRCA2 deletion was found in 0.9% of the screened families. Among unselected breast cancer cases, 3.3% tested positive for BRCA1/3450del4, 2.2% for BRCA1/A1708E, 1.1% for BRCA2/3034del4, and 0.4% for BRCA2/1991del4. Female relatives of carriers of BRCA1/2 founder mutations showed a 5.90 times higher risk of breast cancer, when the woman herself carried a BRCA1 mutation compared to a non-carrier (95% CI 2.01-17.3). The estimated cumulative risk of breast cancer by age 70 years for BRCA1 mutations carriers was 14% (95% CI 5-38) compared to 3% for the general Colombian population (relative risk of breast cancer 4.05). Together with known founder mutations, reported novel variants may ease a cost-effective BRCA1/2 screening in women with Colombian ancestry.
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Project description:BackgroundIt is important to identify biomarkers associated with BRCA mutation in women with early breast cancer (BC) to improve early identification of mutation carriers. Thus, in this study, we examined the protein expression of claudin (CLDN) 3, CLDN4, CLDN7, and E-cadherin. Moreover, we analyzed additional histopathological variables and their associations in familial BC.MethodsImmunohistochemical analysis for CLDNs and E-cadherin was performed on 237 BC cases of three different subsets of BC tumors: 62 from BRCA1 mutation carriers, 59 from BRCA2 mutation carriers, and 116 tumors from patients with BRCA wild type (WT) as controls. Histopathological data were also analyzed in the different subgroups. Logistic regression and receiver operation characteristic (ROC) curve were conducted to investigate factors associated with BRCA tumors.ResultsExpression of CLDN3 positively correlated with BRCA-mutated BC. CLDN3 was expressed in 58% of BRCA1-mutated tumors compared to only 7% in BRCA2-mutated tumors (p < 0.001) and 1% in WT tumors (p < 0.001). CK5 and CK14 expression were also more likely to arise in BRCA1 tumors (44 and 16%, respectively) than in the control group (8 and 4%) (p < 0.001, p = 0.012, respectively). We also found a significantly higher proportion of CK5+ among BRCA1 tumors (44%) in comparison with BRCA2-related BC (8%) (p < 0.001). In addition, there was a significant difference between both groups regarding CK14: positive expression in 16 and 5%, respectively (p = 0.030). CK5 and CK14 did not differ between the BRCA2 group and the WT tumors significantly. In a multivariate regression model, expression of CK5 (Odds ratio (OR): 6.46; 95% confidence interval (CI): 1.52-27.43; p = 0.011), and CLDN3 (OR: 200.48; 95% CI: 21.52-1867.61; p < 0.001) were associated with BRCA1 mutation status.ConclusionsOur data suggests that CLDN3, CK5, and CK14 in combination with ER, PR and HER2 are associated with BRCA1 mutation status.
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