PD64-11 THE PRACTICAL POLYGENIC RISK SCORE IS ASSOCIATED WITH PROSTATE CANCER MORTALITY INDEPENDENT OF PSA BUT HAS LOW PREDICTIVE VALUE

Despite the high prevalence of prostate cancer in older men, the predictive value of a polygenic risk score (PRS) remains uncertain in men aged ≥70 years. We used a 6.6 million-variant PRS to predict the risk of incident prostate cancer in a prospective study of 5701 men of European descent aged ≥70 years (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. The study endpoint was prostate cancer, including metastatic or non-metastatic disease, confirmed by an expert panel. After excluding participants with a history of prostate cancer at enrolment, we used a multivariable Cox proportional hazards model to assess the association between the PRS and incident prostate cancer risk, adjusting for covariates. Additionally, we examined the distribution of Gleason grade groups by PRS group to determine if a higher PRS was associated with higher grade disease. We tested for interaction between the PRS and aspirin treatment. Logistic regression was used to independently assess the association of the PRS with prevalent (pre-trial) prostate cancer, reported in medical histories. During a median follow-up time of 4.6 years, 218 of the 5701 participants (3.8%) were diagnosed with prostate cancer. The PRS predicted incident risk with a hazard ratio (HR) of 1.52 per standard deviation (SD) (95% confidence interval (CI) 1.33–1.74, p < 0.001). Men in the top quintile of the PRS distribution had an almost three times higher risk of prostate cancer than men in the lowest quintile (HR = 2.99 (95% CI 1.90–4.27), p < 0.001). However, a higher PRS was not associated with a higher Gleason grade groups. We found no interaction between aspirin treatment and the PRS for prostate cancer risk. The PRS was also associated with prevalent prostate cancer (odds ratio = 1.80 per SD (95% CI 1.65–1.96), p < 0.001).While a PRS for prostate cancer is strongly associated with incident risk in men aged ≥70 years, the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease.

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Prostate cancer risk prediction using a polygenic risk score

Scientific Reports ◽

10.1038/s41598-020-74172-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Csilla Sipeky ◽

Kirsi M. Talala ◽

Teuvo L. J. Tammela ◽

Kimmo Taari ◽

Anssi Auvinen ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Score ◽

Prostate Cancer Risk ◽

Population Based ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Randomised Study ◽

Additional Information ◽

Increased Risk ◽

Hereditary Factors

Abstract Hereditary factors have a strong influence on prostate cancer (PC) risk and poorer outcomes, thus stratification by genetic factors addresses a critical need for targeted PC screening and risk-adapted follow-up. In this Finnish population-based retrospective study 2283 clinically diagnosed and 455 screen-detected patients from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), 2400 healthy individuals have been involved. Individual genetic risk through establishment of a polygenic risk score based on 55 PC risk SNPs identified through the Finnish subset of the Collaborative Oncological Gene-Environment Study was assessed. Men with PC had significantly higher median polygenic risk score compared to the controls (6.59 vs. 3.83, P < 0.0001). The polygenic risk score above the control median was a significant predictor of PC (OR 2.13, 95% CI 1.90–2.39). The polygenic risk score predicted the risk of PC with an AUC of 0.618 (95% CI 0.60–0.63). Men in the highest polygenic risk score quartile were 2.8—fold (95% CI 2.4–3.30) more likely to develop PC compared with men in the lowest quartile. In the FinRSPC cohort, a significantly higher percentage of men had a PSA level of ≥ 4 ng/mL in polygenic risk score quartile four compared to quartile one (18.7% vs 8.3%, P < 0.00001). Adding the PRS to a PSA-only model contributed additional information in predicting PC in the FinRSPC model. Results strongly suggest that use of the polygenic risk score would facilitate the identification of men at increased risk for PC.

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Broad‐ and narrow‐sense validity performance of three polygenic risk score methods for prostate cancer risk assessment

The Prostate ◽

10.1002/pros.23920 ◽

2019 ◽

Vol 80 (1) ◽

pp. 83-87 ◽

Cited By ~ 1

Author(s):

Hongjie Yu ◽

Zhuqing Shi ◽

Xiaoling Lin ◽

Quanwa Bao ◽

Haifei Jia ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Assessment ◽

Cancer Risk ◽

Risk Score ◽

Prostate Cancer Risk ◽

Cancer Risk Assessment ◽

Polygenic Risk Score ◽

Narrow Sense ◽

Polygenic Risk

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Validation of a prostate cancer polygenic risk score

The Prostate ◽

10.1002/pros.24058 ◽

2020 ◽

Vol 80 (15) ◽

pp. 1314-1321 ◽

Cited By ~ 1

Author(s):

Mary H. Black ◽

Shuwei Li ◽

Holly LaDuca ◽

Min‐Tzu Lo ◽

Jefferey Chen ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Score ◽

Polygenic Risk Score ◽

Polygenic Risk

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Incorporation of Polygenic Risk Score into Guidelines for Inherited Risk Assessment for Prostate Cancer

European Urology ◽

10.1016/j.eururo.2021.04.043 ◽

2021 ◽

Author(s):

Jianfeng Xu ◽

William B. Isaacs

Keyword(s):

Prostate Cancer ◽

Risk Assessment ◽

Risk Score ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Inherited Risk

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The BARCODE1 pilot study targeting men with increased genetic risk of developing prostate cancer: Examining the feasibility of a community-based screening program using polygenic risk score to target screening.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.227 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 227-227

Author(s):

Jana Kathlyn McHugh ◽

Sarah Benafif ◽

Holly ni Raghallaigh ◽

Elizabeth Bancroft ◽

Zsofia Kote-Jarai ◽

...

Keyword(s):

Prostate Cancer ◽

Primary Care ◽

Dna Extraction ◽

Risk Score ◽

Genetic Risk ◽

Population Screening ◽

Low Risk ◽

Polygenic Risk Score ◽

Genetic Profiling ◽

Polygenic Risk

227 Background: A significant proportion of Prostate cancer (PrCa) risk is attributable to heritable risk factors of which only a minority are high risk Mendelian traits. A greater proportion of PrCa is due to the combined effect of multiple low risk variants. There have been approximately 170 single nucleotide polymorphisms (SNPs) identified that are associated with PrCa risk in Europeans. Although each of these confer a low to moderate risk of PrCa, the cumulative risk (polygenic risk score, PRS) of increasing numbers of these risk alleles may confer a substantial relative risk. In PrCa genetic profiling, using PRS, could be used to target population screening to those at highest risk. BARCODE1 is the first study to prospectively review the use of a genetic profile in PrCa screening in the general population in the UK. Methods: Our study invited healthy males aged 55-69 to participate through their Primary Care physicians. Collection kits were mailed to retrieve saliva samples. Genotyping was carried out after DNA extraction using a study specific assay and the PRS was calculated for each participant using the sum of weighted alleles for 130 risk loci. Prostate MRI and Biopsy were then offered to men in the top 10% of the genetic risk profile. Results: 1434 men were invited by letter to participate. The uptake was 26%, of whom 87% of men were eligible for inclusion. Following DNA extraction, genotyping, and quality control checks, data were available for 297 men. 25 participants had PRS in the top 10% and were invited for screening; 19 underwent a prostate MRI, and 18 went on to have a systematic (+/- targeted prostate biopsy. There were 7 diagnoses of PrCa (38.9%). The cancers detected were low-risk and are being managed with Active Surveillance (AS). Results of the first year of follow up will be presented and an update of the main study which aims to recruit 5000 men. Conclusions: The BARCODE1 pilot has shown the feasibility of this population-based study, with an overall uptake of 26% and a cancer incidence of nearly 40%. We have identified approximately 70 Primary care providers who have contributed to the transition to the full BARCODE1 study, which will aim to recruit 5,000 men. The BARCODE1 study results will be important in defining the role of PRS genetic profiling in targeted PrCa population screening. Clinical trial information: IRAS257684.

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