부산대학교 도서관

BackgroundBOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) for breast cancer and the epithelial tubo-ovarian cancer (EOC) models included in the CanRisk tool (www.canrisk.org) provide future cancer risks based on pathogenic variants in cancer-susceptibility genes, polygenic risk scores, breast density, questionnaire-based risk factors and family history. Here, we extend the models to include the effects of pathogenic variants in recently established breast cancer and EOC susceptibility genes, up-to-date age-specific pathology distributions and continuous risk factors.MethodsBOADICEA was extended to further incorporate the associations of pathogenic variants in BARD1, RAD51Cand RAD51Dwith breast cancer risk. The EOC model was extended to include the association of PALB2pathogenic variants with EOC risk. Age-specific distributions of oestrogen-receptor-negative and triple-negative breast cancer status for pathogenic variant carriers in these genes and CHEK2and ATMwere also incorporated. A novel method to include continuous risk factors was developed, exemplified by including adult height as continuous.ResultsBARD1, RAD51Cand RAD51Dexplain 0.31% of the breast cancer polygenic variance. When incorporated into the multifactorial model, 34%–44% of these carriers would be reclassified to the near-population and 15%–22% to the high-risk categories based on the UK National Institute for Health and Care Excellence guidelines. Under the EOC multifactorial model, 62%, 35% and 3% of PALB2carriers have lifetime EOC risks of <5%, 5%–10% and >10%, respectively. Including height as continuous, increased the breast cancer relative risk variance from 0.002 to 0.010.ConclusionsThese extensions will allow for better personalised risks for BARD1, RAD51C, RAD51Dand PALB2pathogenic variant carriers and more informed choices on screening, prevention, risk factor modification or other risk-reducing options.