Within-family analysis of PRS₃₁₃: insights into breast cancer risk prediction

Polygenic risk scores (PRS) incorporate numerous genetic variants, each with a small impact on cancer pathogenesis, to provide personalized risk assessments. This study investigated, the applicability of PRS₃₁₃ for breast cancer risk both in the general population and within families (patients vs different groups of their relatives) from the Tehran Cardiometabolic Genetic Study (TCGS)cohort. The cohort included 72 breast cancer cases and 2,603 controls. PRS₃₁₃ showed no significant difference between cases and controls, and logistic regression indicated no significant association between PRS₃₁₃ and breast cancer risk (OR: 1.24, 95 % CI: 1.002-1.54). However, PRS differences between patients and their first- and second-degree relatives showed strong statistical significance. The monogenic variant analysis identified 21 loss-of-function (LOF) variants in the cohort, but only one (BRCA2 9976A > T) was common among breast cancer cases. Our findings highlight the importance of within-family analysis of PRS and the challenges of applying European-derived PRS models to diverse populations.