Familial Risk Stratification Across Cancer Syndromes Using Fam3PRO.
PURPOSE Quantitative assessment of the risk of inherited cancer susceptibility should reflect the growing number of well-documented gene-cancer associations beyond single syndromes, to increase efficiency when identifying candidates for genetic testing and early detection. METHODS We validate Fam3PRO, a computationally efficient Mendelian risk prediction methodology and platform that supports constructing models with an arbitrary number of genes and cancers, on three independent multi-ethnic panel cohorts. Fam3PRO was trained using population-level parameters from existing literature for 21 genes and 17 cancers. RESULTS Fam3PRO provides discrimination and calibration comparable to the widely-adopted syndrome-specific models BRCAPRO and MMRpro, for genes associated with Breast-Ovarian and Lynch syndromes. Furthermore, when assessing the probability of being heterozygous for at least one pathogenic variant in any of the 21 genes, Fam3PRO has a discrimination of 0.64 (95% C.I. 0.62-0.67) and a calibration (observed divided by expected) of 1.13 (95% C.I. 1.05-1.22) in the combined cohort. At probability thresholds of 2.5% and 5%, Fam3PRO identifies more individuals at high risk of being heterozygous for pathogenic variants in any of the 21 genes than BRCAPRO and MMRpro. CONCLUSION Fam3PRO provides a validated approach for familial risk stratification across a broad spectrum of cancer types, including estimates of carrier probabilities and future cancer risk.