Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men

Abstract

Background: Clinical variables—age, family history, genetics—are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death. Methods: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n=3,279; 2,163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests. Results: Median age at last follow-up/prostate cancer death were 78.0 (IQR: 72.3–84.1) and 81.4 (75.4–86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95%CI 2.78–4.17]), family history (HR 1.72 [1.46–2.03]), alcohol (HR 1.74 [1.40–2.15]), diabetes (HR 0.53 [0.37–0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99–2.97]), family history (HR 1.73 [1.48–2.03]), alcohol (HR 1.45 [1.19–1.76]), diabetes (HR 0.62 [0.42–0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer ( p <10 −15 ). Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.

Prostate cancer risk stratification improved across multiple ancestries with new polygenic hazard score

“…While individuals with high polygenic risk may also develop low-grade prostate cancer in their lifetime, the time-to-event analysis applied here shows that high genetic risk confers a greater hazard for prostate cancer death. This finding is consistent with prior reports, though the effect size is larger with PHS290 2,16,33 .…”

“…This was true in four separate testing sets of varied genetic ancestry (Asian, African, European). Additionally, PHS290 was associated with lifetime prostate-cancer-specific mortality in a population-based cohort 16 . Hazard ratios with PHS290 are larger for each of these associations than those reported for previous versions of PHS 2,8 , demonstrating the value of incorporating SNPs from genome-wide meta-analysis and fine-mapping.…”

“…The combination of family history and PHS performed better than family history, alone, for clinically significant prostate cancer (and for any prostate cancer) in each of the four testing datasets (log-likelihood p<10 -16 ; Table 2). Additionally, family history and PHS together performed better than family history, alone, for fatal prostate cancer in the COSM dataset (log-likelihood p< [10][11][12][13][14][15][16] ).…”

“…The available data were split into a training dataset and four testing datasets, taking into account prior power analyses and PHS association results 7,15,16 for both cases and controls (n=6,411: 4,828 controls and 1,583 cases) 18 .…”

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

“…To assess the added value of PHS290 beyond commonly used clinical risk factors, we tested a multivariable Cox proportional hazards model with ancestry group, family history, and PHS290 7,9,19 . This combined model was limited to the 374,455 participants who provided family history information in baseline survey data.…”