Incorporation of polygenic risk score into guidelines for inherited risk assessment for prostate cancer

Two experts commented on the practical utility of germline genetic testing for the risk for prostate cancer that stem from an important recent article¹ based on a study of more than 80,000 men in the U.K. Biobank on the combined effects of rare, highly-penetrant genetic mutations and common germline variants (called “SNPs”) that are associated with the risk for prostate cancer (See the article on pages 1-3 and page 5 on the History of PSA Screening). 

There were three important findings.  First, the rare, highly-penetrant mutations in the HOXB13 and CHEK2 genes are predominantly found in men who have a low-risk score based on the common genetic variants (“SNPs”).  Second, they found that rare mutations in only 4 genes (HOXB13, BRCA2, ATM, and CHEK2) are significantly associated with prostate cancer risk.  Third, testing for both the rare mutations and common SNPs in a polygenic risk score helps differentiate the absolute risk for being diagnosed with prostate cancer by age 85, ranging from 2% for men with no rare mutations and low polygenic risk score to 56% for men having both a rare, highly-penetrant mutation and a high polygenic risk score. The first finding is novel and needs further replication because rare mutations and polygenic risk scores previously were thought to be independent of one another. The last two findings are ready to be translated into clinical practice.

j.eururo.2021.04.043