Non-random transmission of mutant alleles to female offspring of BRCA1 carriers in Poland

Abstract

Constitutional mutations in the BRCA1 gene predispose to an autosomal dominant syndrome of breast and ovarian cancer. The lifetime penetrance of BRCA1 gene mutations is high; approximately 50% of women with mutations will be affected by cancer by the age of 50 years, and over 80% of women with mutations will be affected with cancer by the age of 75 years.1 At birth, it is expected that 50% of the children of a carrier parent will inherit a mutant allele. If the mortality in carriers is higher in carriers than in non-carriers, then the proportion of carriers among offspring is expected to decline with age. Similarly, among unaffected women, the proportion of carriers is expected to decline with age. For example, if the gene is 50% penetrant by by the age of 50 years, then one third of a sample of healthy 50 year old female offspring of carriers are expected to be carriers. Under the assumption that a mutant allele is transmitted to 50% of offspring, it is therefore possible to estimate age-specific penetrance values of the BRCA1 gene by counting the relative number of carriers and non-carriers in a sample of healthy offspring, of varying ages, of carrier parents. Three founder mutations in BRCA1 are common in Poland (5382insC, C61G, and 4153delA).2 In an attempt to estimate the age-specific penetrance of these three mutations, we systematically reviewed the genotypes of mothers and daughters in a selected group of …