Association of BRCA1/2 mutations with FMR1 genotypes: effects on menarcheal and menopausal age.

OBJECTIVE: Female BRCA (breast cancer gene)-1 and BRCA-2 mutations are significantly associated with risk of developing breast and ovarian cancers, in turn, associated with female infertility. BRCA-1 mutations have also been associated with occult primary ovarian insufficiency (OPOI), as have different mutations of the FMR1 gene. We, therefore, hypothesized that FMR1 genotypes may be associated with menarcheal and menopausal ages of BRCA mutation carriers. PATIENTS: We compared the FMR1 genotype and sub-genotype distribution in 99 BRCA1/2 positive women and in 182 healthy women without a known history of familial breast and ovarian cancer and searched for associations with age at menarche and menopause. T-test was used to assess differences in menarcheal and menopause ages, with times of menarche and menopause as continuous variables.
RESULTS: Women with BRCA1/2 mutations showed significantly different FMR1 genotype and sub-genotype distributions when compared with the control group (p<0.001). This result remained stable in a sub-group analysis of Caucasian BRCA1/2 carriers and healthy controls (p<0.001). In addition, BRCA1/2 carriers indicated a trend toward shorter reproductive lifespan (p=0.18).
CONCLUSIONS: Our data confirm the previously reported highly skewed distribution of FMR1 genotypes and sub-genotypes toward a high preponderance of low FMR1 alleles in BRCA1/2 carriers. We could demonstrate that BRCA-1 mutations are associated with an earlier onset of menopause compared to BRCA-2 carriers, although the distribution of the het-norm/low genotype is similar in both groups. Our findings suggest that there may be other factors beside the genotype that has an influence on menarche and especially menopause age in BRCA mutation carriers.