BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study.
BACKGROUND
An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative.


METHODS
Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants.


RESULTS
Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74-3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested.


CONCLUSIONS
Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure.
['Kitson|Sarah J|SJ|', 'Bafligil|Cemsel|C|', 'Ryan|Neil A J|NAJ|', 'Lalloo|Fiona|F|', 'Woodward|Emma R|ER|', 'Clayton|Richard D|RD|', 'Edmondson|Richard J|RJ|', 'Bolton|James|J|', 'Crosbie|Emma J|EJ|', 'Evans|D Gareth|DG|']
D000328:Adult D019313:BRCA1 Protein D024682:BRCA2 Protein D018269:Carcinoma, Endometrioid D015331:Cohort Studies D018284:Cystadenocarcinoma, Serous D016208:Databases, Factual D016889:Endometrial Neoplasms D005260:Female D005500:Follow-Up Studies D005787:Gene Frequency D020022:Genetic Predisposition to Disease D018095:Germ-Line Mutation D006579:Heterozygote D006801:Humans D015994:Incidence D008875:Middle Aged D012307:Risk Factors D006113:United Kingdom D055815:Young Adult
BRCA1 BRCA2 Endometrial cancer Risk Serous endometrial cancer