Abstract
The age at first-time pregnancy has been long recognised as a risk factor for breast cancer, but the mechanism underlying this have not been identified yet. By looking at the healthy breast, we hypothesise that both age and parity affect the mutational burden in the mammary epithelium, and the interplay between the two variables influences the probability of acquiring oncogenic mutations at different rates in the parous and nulliparous breast.
Whole-genome sequencing analysis from the laser-captured epithelial and stromal cells from 20 healthy parous (early and late) and nulliparous breast, revealed that the genomic landscape of the normal breast epithelium is characterised by a high number of somatic mutations (from 200,000 to 750,000 SNPs) and by the presence of mutations in breast cancer drivers (up to and average of 100 hits/gene). While the nulliparous breast is characterised by little variation in the mutational burden across the years, in the parous breast the burden increases with age, with comparable values to the nulliparous breast for the early parity group and significantly higher levels for older parity status. In particular, mutational hits in the driver genes are, irrespectively of age, significantly higher in the parous breast (p<0.005). The increase in mutation of the parous breast in the older age groups is linked to the presence of significant smaller clones, estimated on variant allele frequencies compared to nulliparous breast. This confirms that driver genes are already mutated in the healthy breast, and that the higher proliferation of the parous breast contributes to the higher probability of a mutated cancer clone to expand within the mammary epithelium.
The parous breast epithelium and stroma are characterised by the presence of significantly higher frequency of the 3’UTR variants and the start loss mutations. We propose that the disparity in the risk of developing BC between the groups could be because of the mutations in these regulatory regions. Further validation of these SNPs will allow us to elucidate the exact function of these SNPs, which will have an implication in understanding the disparity in the risk of breast cancer based on age and parity status.