Modest risk single nucleotide polymorphism polygene in breast cancer susceptibility

During the 1990s, the search for breast cancer susceptibility genes identified several high-risk genes such as BRCA1&2, TP53, and PTEN. The late 1990s and early 2000s saw identification of the first intermediate risk genes, ATM, CHEK2, and PALB2. With time, however, the likelihood of identifying new high-risk genes is diminishing; on the other hand, the technology for hypothesis free, genome-wide identification of intermediate risk genes is still being developed. During the mid-2000s, the hunt for the genetic basis of breast cancer shifted toward genome-wide searches for modest risk breast cancer associated single nucleotide polymorphisms (SNPs). Here, we study a panel of 16 such SNPs as a polygene. We demonstrated that the polygene model works well for this panel, and that when viewed as a polygene, the composite risk for some individuals rises to a level comparable to an intermediate risk gene. We also find that the polygene model seems to better differentiate case-control status with increasing numbers of SNPs; therefore, we expect that the more SNPs that are added to the polygene model, the more accurately risk will be differentiated in the composite odds ratio (OR) and the closer the model will move toward medically actionable utility.