---

Background

Polygenic risk scores (PRS) estimate an individual’s germline genetic predisposition to a quantitative trait and/or risk of disease. Several PRS have been developed for cancer risk with the goal of improved risk screening. Here, we sought to establish whether PRS for cancer risk and other common traits may influence survival for patients with cancer.

Methods

We conducted a PRS survival analysis using 23,770 cancer patients of European ancestry from the Dana-Farber Cancer Institute Profile cohort.

Results

We identified an association between PRS for breast cancer risk and longer patient survival (HR = 0.89 (95% CI: 0.84–0.95), p = 1.50 × 10^–4, < 5% FDR), implying that individuals at high genetic risk had better outcomes. High PRS individuals were also significantly less likely to harbor somatic TP53 mutations, consistent with having less aggressive tumors. This association persisted when including tumor grade and became more protective when restricting to ER-negative tumors (HR = 0.78 (95% CI: 0.68–0.89), p = 1.69 × 10^–4). Potential confounders such as hormone receptor status, age, grade, stage, and ER-targeted therapy did not fully explain this association, nor was there statistical evidence of index event bias at individual variants. We did not observe significant associations between cancer risk and survival for other cancers, suggesting that this mechanism may be largely unique to breast cancer. However, we did observe associations between shorter survival and type 2 diabetes, bipolar, and pancreatitis PRS (1% FDR).

Conclusions

These findings suggest that higher germline risk may predispose individuals to less aggressive breast cancer tumors and provide novel insights into breast cancer development and prognosis.