Genetics in medicine : official journal of the American College of Medical Genetics · 2026
Familial Risk Stratification Across Cancer Syndromes Using Fam3PRO.
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Liang Jane W, Idos Gregory E, Hong Christine, Shannon Kristen M, Bear Lauren M, Bonner Joseph D, Lindsey Sidney, Morales Pichardo Jennifer, Guan Zoe, McCarthy Anne Marie, Gruber Stephen B, Braun Danielle, Parmigiani Giovanni
Аннотация
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.
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.