Polygenic Risk Score as a Predictor of Mammary Carcinogenesis in NMU-Treated Mice

Background and Objective: Polygenic risk scores (PRS) predict breast cancer susceptibility in humans; however, their functional impact on tumour progression has not been experimentally validated. The present work aimed to evaluate the impact of a polygenic risk score in an in vivo model of mammary carcinogenesis. The specific objectives were to determine whether an animal-based PRS (aPRS): Alters the timing of tumour initiation following NMU exposure; influences tumour multiplicity and growth; affects the likelihood of metastasis; predicts overall survival; and improves model discrimination when incorporated with standard predictors. Materials and Methods: An animal-based polygenic risk score (aPRS) was constructed using murine homologues of human breast cancer susceptibility loci and its predictive value was evaluated in an N-nitrosomethylurea (NMU) induced mammary carcinogenesis model. Female mice (n = 120) were stratified into aPRS tertiles and monitored for 365 days. Assessed outcomes included tumour latency, multiplicity, growth, metastasis, and survival. Statistical analyses comprised Cox proportional hazards regression, mixed-effects models, and ROC-based discrimination analyses, with all tests evaluated at a two-sided significance level of 0.05. Results: Mice in the high-aPRS group developed tumours earlier (median 290 vs. 330 vs. >365 days), exhibited increased tumour multiplicity (IRR 1.42; 95% CI, 1.18-1.71), and demonstrated faster tumour growth (β = 0.21, p<0.01). Metastatic incidence was higher (OR 1.78 per 1 SD increase, p<0.05), accompanied by poorer overall survival (log-rank p<0.001). Inclusion of aPRS improved predictive discrimination (C-index 0.74 vs. 0.61; ΔAUC+0.07). Conclusion: The aPRS influences tumour initiation, progression, and survival in an in vivo setting, thereby linking genomic risk prediction with mechanistic aspects of oncology.