BACKGROUND
We previously developed a tier-based germline classification using the National Comprehensive Cancer Network (NCCN)-recommended DNA damage repair (DDR) genes and KLK3 I179T to predict prostate cancer (PCa)-specific mortality (PCSM). To provide an easier-to-use single inherited risk score while preserving gene-specific effects, we developed GenProb-PCSM.
METHODS
We analyzed 14,644 men with incident PCa from the UK Biobank. The cohort was randomly divided into training (60%) and independent testing (40%) datasets. GenProb-PCSM was developed in the training cohort by integrating pathogenic variants in ten NCCN-recommended DDR genes and the KLK3 I179T variant using gene-specific weights derived from Fine-Gray competing-risk models. Performance was evaluated in the independent testing cohort by discrimination, calibration, and risk stratification. Secondary analyzes evaluated metastatic progression and the composite endpoint of metastatic progression and/or PCSM.
RESULTS
Among 14,644 men with incident PCa, 1,581 died from PCa. GenProb-PCSM remained significantly associated with PCSM in the independent testing cohort (HR per SD, 1.18; 95% CI, 1.12-1.24; p < 0.001). Using predefined risk thresholds derived from the training cohort, patients in the intermediate- and high-risk groups had significantly increased risks of PCSM compared with the low-risk group (HR 1.49, 95% CI 1.22-1.84; and HR 4.04, 95% CI 2.58-6.33, respectively). GenProb-PCSM also predicted independent metastatic progression and the composite endpoint of metastatic progression and/or PCSM.
CONCLUSIONS
GenProb-PCSM transforms complex germline findings into a single inherited risk score for PCSM and metastatic progression. Its simplicity and preservation of gene-specific effects may facilitate clinical implementation of germline prognostic assessment in PCa.
Jun Wei, Zhu-Qing Shi, Lucy Lu et al.· The Prostate· 0 citations
IMPORTANCE
Patients diagnosed with breast cancer (BCa) are at increased risk of multiple common diseases; however, the spectrum of these diseases and the contribution of inherited genetic susceptibility remain incompletely characterized.
METHODS
We evaluated 15 common diseases and tested their associations with BCa exposure and disease-specific polygenic risk scores (PRS) in the UK Biobank (UKB; N = 254,736). Analyses were performed using cause-specific Cox proportional hazards models within a full-cohort framework, with time-updated BCa status, delayed entry at study recruitment, and age as the underlying time scale.
RESULTS
After recruitment, incident BCa was diagnosed in 11,386 women (4.47%), including 2,742 (24.08%) with metastatic BCa. Patients with BCa had an increased risk of nine diseases spanning cardiovascular, metabolic, and neuropsychiatric domains (P<0.003, Bonferroni-corrected). Elevated risks were generally observed among patients with both early staged and advanced BCa. Inherited susceptibility further stratified disease risk, with the highest risks observed among patients with BCa with elevated disease-specific PRS. For example, compared with women without BCa, the hazard ratio (HR; 95% CI) for osteoporosis was 2.33 (2.15-2.52) among women with any BCa, 2.38 (2.18-2.59) among those with non-metastatic BCa, and 2.12 (1.78-2.54) among those with metastatic BCa; the HR was 4.48 (3.99-5.02) among patients with BCa in the highest quartile of osteoporosis-specific PRS (all P<0.001). In contrast, BCa was not significantly associated with risk of coronary artery disease.
CONCLUSION
BCa and inherited genetic susceptibility jointly contribute to increased risk of multiple common diseases, supporting the integration of genetic risk stratification into survivorship care.
Annabelle Ashworth, Zhu-Qing Shi, Huy Tran et al.· JNCI Cancer Spectrum· 0 citations
Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.
Sierra R. Broad, Jun Wei, Keri L. Denson et al.· Annals of Thoracic Surgery· 0 citations
An integrated continuum genetic risk model, GenProb-PCa, improves PCa risk stratification beyond binary approaches by capturing heterogeneity in inherited risk and may enable more precise risk-based screening strategies.
Zhu-Qing Shi, A. Mulford, Jun Wei et al.· Journal of Medical Genetics· 0 citations
Germline PVs in NCCN-recommended DDR genes and the KLK3 I179T variant identify a subset of men at elevated risk of PCSM, including those with apparently localized disease.
Lucy Lu, Julian Xu, Zhu-Qing Shi et al.· Prostate Cancer and Prostati...· 1 citation
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