Comprehensive Breast Cancer Risk Assessment for CHEK2 and ATM Pathogenic Variant Carriers Incorporating a Polygenic
Shannon Gallagher1, Elisha Hughes1, Allison W Kurian2
1Myriad Genetics Inc, Salt Lake City, UT.
JCO Precision Oncology
|July 29, 2021
Summary
Breast cancer risk for CHEK2 and ATM pathogenic variant carriers can be better predicted using a polygenic risk score (PRS) combined with clinical factors. This approach allows for more precise screening and prevention strategies for carriers.
Area of Science:
- Genetics
- Oncology
- Risk Assessment
Background:
- Breast cancer risk is influenced by genetic factors, including pathogenic variants (PVs) in genes like CHEK2 and ATM.
- Individual clinical factors and polygenic risk scores (PRS) can modify the risk associated with these PVs.
- Accurate risk prediction is crucial for tailoring screening and prevention strategies in high-risk individuals.
Purpose of the Study:
- To develop and validate comprehensive risk prediction models for women of European ancestry carrying CHEK2 or ATM pathogenic variants (PVs).
- To integrate PV status, polygenic risk score (PRS), and individual clinical variables into a combined risk assessment model.
- To evaluate the potential of these models for refining breast cancer screening and prevention strategies.
Main Methods:
- Utilized deidentified clinical records from 358,095 women of European ancestry tested with a multigene panel.
- Developed models incorporating CHEK2 PV carriers (n=4,286), ATM PV carriers (n=2,666), and controls (n=351,143).
- Calculated odds ratios (ORs) using multivariable logistic regression and a Fixed-Stratified method for combined risk estimates incorporating PV status, PRS, and Tyrer-Cuzick model.
Main Results:
- CHEK2 and ATM PV carriers showed increased breast cancer risk (ORs 2.01 and 1.83, respectively).
- PRS per standard deviation was associated with increased risk in both CHEK2 (OR 1.51) and ATM (OR 1.45) PV carriers.
- The combined model stratified remaining lifetime risk (RLR) for CHEK2 carriers (24.2% low, 63.8% medium, 12.0% high) and ATM carriers (31.5% low, 58.5% medium, 9.7% high).
Conclusions:
- Integrating polygenic risk scores, clinical factors (Tyrer-Cuzick), and pathogenic variant status provides a more precise breast cancer risk assessment for CHEK2 and ATM carriers.
- This comprehensive approach has the potential to significantly improve the direction of personalized screening and prevention strategies.
- Enhanced risk stratification enables tailored management plans for individuals with CHEK2 and ATM pathogenic variants.
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