Effects of BRCA1 and BRCA2 mutations on female fertility

Abstract

Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into multi-generational pedigrees within the Utah Population Database were used to identify putative obligate carriers. We find that women born before 1930 who are mutation carriers have significantly more children than controls and have excess post-reproductive mortality risks. They also have shorter birth intervals and end child-bearing later than controls. For contemporary women tested directly for BRCA1/2 mutations, an era when modern contraceptives are available, differences in fertility and mortality persist but are attenuated. Our findings suggest the need to re-examine the wider role played by BRCA1/2 mutations. Elevated fertility of female mutation carriers indicates that they are more fecund despite their elevated post-reproductive mortality risks.

Figure 1.

(a) Effects of BRCA1/2 mutation status on number of children ever born, based on ordinary least squares (OLS) regression controlling for birth year, age at first birth and number of deceased children (who died by age 5). (b) Effects of BRCA1/2 mutation status on age at first birth (AFB) and age at last birth (ALB), based on OLS regressions controlling for birth year and age at marriage (and AFB for the ALB model). (c) Effects of BRCA1/2 mutation status on first birth interval (FBI) and average birth interval (ABI), based on OLS regressions controlling for birth year and age at first marriage. (d) Survival probabilities past age 45 by BRCA1/2 mutation status for women born before 1930, based on Cox proportional hazard regressions controlling for birth year. Models for women born before 1930 also controlled for LDS status. Dark grey bars or lines denote carrier and light grey bars or lines denote control.