Breast and prostate cancer risk: the interplay of polygenic risk, rare pathogenic germline variants, and family history

Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. Heterozygotes or non-heterozygotes of PV in moderate to high cancer risk genes, 2. PRS strata, 3. with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio (OR) across groups and the cumulative incidence through life. Results Cumulative incidence by age 70 among non-heterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast and prostate cancer, respectively. Among PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history is always associated with an increased cancer OR. Conclusion PRS provides a meaningful risk gradient leading alone to a cancer risk comparable to PV in moderate risk genes while acting as risk modifier for high-risk genes. Including family history beside PV and PRS further improves cancer risk stratification.