Prostate cancer is a significant health concern for men worldwide, and early detection plays a crucial role in improving outcomes. Researchers have now discovered that considering a man's genetics can enhance the predictive value of the most widely used biomarker in prostate cancer detection, prostate-specific antigen (PSA). By incorporating genetic variants, scientists aim to reduce the risk of prostate cancer overdiagnosis and improve the identification of aggressive forms of the disease.
Understanding PSA and Its Limitations
PSA is an enzyme produced by the prostate gland, responsible for breaking down gel-forming seminal proteins to release motile sperm. Elevated PSA levels can indicate prostate epithelial tissue disruption caused by tumors. However, increased PSA concentrations may also result from factors such as inflammation, infection, benign hyperplasia, older age, and enlarged prostate volume. Consequently, low PSA levels do not guarantee the absence of prostate cancer, while elevated levels alone are insufficient for a conclusive cancer diagnosis. PSA testing is estimated to lead to overdiagnosis in 20% to 60% of cases.
Harnessing Genetic Variants for Improved Detection
In a recent study published in the journal Nature Medicine, researchers analyzed the genetic profiles of over 95,000 men to identify genetic variants that affect serum PSA levels. The team discovered 128 genetic variants, with 82 being novel, that impact PSA levels. Leveraging these findings, they developed a PSA polygenic score (PGS) capable of explaining approximately 10% of the inherent variation in PSA levels.
"The polygenic score captured each individual's genetic predisposition to high PSA levels," explained co-author Rebecca Graff, ScD, from the University of California at San Francisco. Importantly, the PGS was strongly associated with PSA levels in validation cohorts and demonstrated no correlation with prostate cancer, confirming its representation of benign PSA variation.
Enhancing Biopsy Referral Decisions
To further refine prostate cancer detection, the researchers combined data from five studies and performed genome-wide analyses of PSA levels in men who had never been diagnosed with prostate cancer and had PSA levels of 10 ng/ml or less. Through meta-analysis within ancestry groups and subsequent consolidation across populations, they obtained a sample size of 95,768 individuals.
Utilizing the 128 genome-wide significant associations, the team then developed a PSA polygenic score capable of explaining 9.61% of constitutive PSA variation. By applying the polygenic score correction factor to a real-world cohort at Kaiser Permanente, they assessed its impact on biopsy referrals. The results demonstrated that correcting PSA levels using the polygenic score improved biopsy referral decisions, potentially avoiding 31% of negative prostate biopsies. Moreover, it led to 12% fewer biopsies in patients with prostate cancer, primarily those with low-grade tumors.
Enhanced Predictability and Personalized Screening Guidelines
Notably, genetically adjusted PSA levels were more predictive of aggressive prostate cancer compared to unadjusted PSA levels, with an odds ratio of 3.44 versus 3.31 in 106 cases and 23,667 controls. Co-author Linda Kachuri, PhD, from Stanford Cancer Institute, expressed optimism regarding the potential impact of genetic correction: "We showed that genetic correction of PSA levels has the potential to both reduce unnecessary biopsies and improve our ability to detect tumors with a more aggressive profile."
However, the authors acknowledge the challenge of developing a polygenic score that performs consistently across different ancestry groups. They observed variations between individuals of European and African heritage. Nevertheless, they assert that leveraging polygenic scores to personalize diagnostic biomarkers, such as PSA, opens new avenues for translating genomic discoveries into clinical practice.
The integration of genetic information into prostate cancer detection represents a significant advancement in the field.
By considering genetic variants, the predictive value of PSA levels can be substantially improved, reducing the risk of overdiagnosis and enhancing the identification of aggressive tumors. The findings from this study provide promising insights for developing informative screening guidelines and narrowing the diagnostic gray area in PSA testing.
(Inside Precision Medicine -[https://www.insideprecisionmedicine.com/topics/oncology/prostate-cancer/genetics-improves-prostate-cancer-detection/)