BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk

Abstract

BackgroundDeleterious mutations in the BRCA genes are responsible for a small, but significant, proportion of breast and ovarian cancers (5 - 10 %). Proof of de novo mutations in hereditary breast/ovarian cancer (HBOC) families is rare, in contrast to founder mutations, thousands of years old, that may be carried by as much as 1 % of a population. Thus, if mutations favoring cancer survive selection pressure through time, they must provide advantages that compensate for the loss of life expectancy.MethodThis hypothesis was tested within 2,150 HBOC families encompassing 96,325 individuals. Parameters included counts of breast/ovarian cancer, age at diagnosis, male breast cancer and other cancer locations. As expected, well-known clinical parameters discriminated between BRCA-mutated families and others: young age at breast cancer, ovarian cancer, pancreatic cancer and male breast cancer. The major fertility differences concerned men in BRCA-mutated families: they had lower first and mean age at paternity, and fewer remained childless. For women in BRCA families, the miscarriage rate was lower. In a logistic regression including clinical factors, the different miscarriage rate and men's mean age at paternity remained significant.ResultsFertility advantages were confirmed in a subgroup of 746 BRCA mutation carriers and 483 non-carriers from BRCA mutated families. In particular, female carriers were less often nulliparous (9.1 % of carriers versus 16.0 %, p = 0.003) and had more children (1.8 ± 1.4 SD versus 1.5 ± 1.3, p = 0.002) as well as male carriers (1.7 ± 1.3 versus 1.4 ± 1.3, p = 0.024).ConclusionAlthough BRCA mutations shorten the reproductive period due to cancer mortality, they compensate by improving fertility both in male and female carriers.

The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?

“…However, we observed that the increase in offspring number was paralleled by a slight decrease in the number of spontaneous, not induced, abortions. Interestingly, a higher birth rate and lower spontaneous abortion frequency were also reported for female carriers of deleterious mutations in the DNA repair genes BRCA1 und BRCA2 [50–52]. From an evolutionary point of view, this link is explicable in terms of genetic variation in DNA repair genes that predisposes to cancer causing better survival under adverse environmental conditions [53].…”

A framework for how environment contributes to cancer risk

“…; Kwiatkowski et al . ). Although many factors may be involved, da Silva (da Silva ) used mathematical models to show that considerable augmentations in fecundity associated with weak negative impacts on fitness (resource transfers or the ‘grandmother effect’; Croft et al .…”

Endokrine Interventionen bei Frauen mit BRCA-1/2-Mutation

“…Founder mutations are usually thousands of years old and might be carried by 1 % of a population. According to the data of Kwiatkowski et al [61] female carriers are less often nulliparous and had more children. They concluded that-although BRCA mutations shorten the reproductive period due to cancer mortality-both male and female carriers are more fertile [61].…”

“…According to the data of Kwiatkowski et al [61] female carriers are less often nulliparous and had more children. They concluded that-although BRCA mutations shorten the reproductive period due to cancer mortality-both male and female carriers are more fertile [61]. However, Finch et al and others were not able to find a difference in parity between BRCA mutation carriers and non-carriers.…”