Using this approach, they identified 9 single nucleotide polymorphisms (SNPs) that were significantly associated with increased risk of breast cancer after radiation therapy (the estimated per-allele interaction odds ratios [IORs] for these 9 SNPs ranged from 1.6 to 2.2; false discovery rate, <20%). From these 9 loci, they created a polygenic risk score (PRS) to predict future breast cancer. Individuals with the highest risk scores had 1.6-fold increase in breast cancer risk than those with the lowest scores.
The predictive power of the PRS transcended other factors, including age at the time of radiation exposure, as well as exposure to gonadotoxic therapy. Destruction of the ovaries by radiation or alkylating chemotherapy can reduce estrogen production and lower the risk of later breast cancer. Yet the PRS retained its predictive value even among women in this low-risk group.
The researchers also evaluated a breast cancer polygenic risk score (BC-PRS), developed for the general population, containing 77 SNPs. “Remarkably, we observed a 4-fold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS,” they wrote. “These results indicate that the effects of radiation exposure and common susceptibility variants, summarized in the PRS, combine approximately multiplicatively.”
Thus, the BC-PRS itself can already help identify those with the greatest need for breast cancer surveillance after chest radiation, even as the new 9-gene radiation-specific PRS awaits independent validation.
Among the newly identified radiation-interaction variants, the strongest association was with a variant in the long noncoding RNA PVT1, a neighbor of c-MYC. Previous studies have suggested that amplification of this region, including both PVT1 and c-MYC, could be a key event in radiogenic breast cancer. PVT1 also appears to regulate the oncogenic activity of MYC.
“It’s really no surprise that this variant is localized to that region,” said Dr Allan. “There is now quite a lot of evidence that’s accumulated that’s implicating this region as a major determinant in breast cancer following radiation exposure.”