There are many areas in life where high scores matter. Team sports rely on points to determine winners. Scores on achievement tests can determine if applicants are accepted into their first choice of college or university. Individual performance scores in Olympic events raise hopes of earning a gold medal.

However, there’s a new kid in the world of scores, and a high score that does not bode well for those who get it. It’s called a polygenic risk score (PRS), and it’s only been in existence since first developed in 2007. What made it possible was completion of the Human Genome Project in 2003, which “gave us the ability to read nature’s complete genetic blueprint for a human.” The project identified over 20,000 coding genes that have known biologic functions, and many more non-coding genes that may or may not have significant functions.

Of special interest is gene variants that link to disease. MedlinePlus defines a gene variant as a “permanent change in the DNA sequence that makes up a gene. This type of genetic change used to be known as a gene mutation, but because changes in DNA do not always cause disease, it is thought that gene variant is a more accurate term.” There are literally millions of possible variants but most are harmless. By analyzing the genome of a person with a given disease, scientists have identified many variants connected with it. This is where risk scoring comes in.

To obtain a patient’s PRS, a lab analyzes a sample of his blood or saliva. “Polygenic” means many genes. The risk score equals the total number of the patient’s disease-associated variants. The higher the score, the greater the inherited risk for the disease in question. The PRS for prostate cancer (PCa) in particular is a work in progress, as more variants linked with PCa are discovered, e.g., in 2023 a multinational team published their “genome-wide association study of 156,319 prostate cancer cases and 788,443 controls” that included multi-ancestry groups.^[i] They found 187 new PCa risk variants and thus a new PRS score.

PRS and PCa: bad news, good news

In July 2024, the Journal of the American Medical Association (JAMA) carried a study by Plym, et al. linking PRSs with PCa.^[ii] Using a PRS comprised of 400 genetic variants linked to PCa, the team correlated high scores with increased risk for developing PCa. They write, “PRSs of common genetic variants provide robust risk stratification for prostate cancer incidence as well as prostate cancer mortality across different populations and ancestry groups.” In other words, PRSs for PCa gene variants can help screen which men are at higher risk, and how likely PCa will be the cause of death.

Without prostate cancer at inclusion and with lifestyle data in 2 prospective cohort studies in Sweden and the US, the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS), followed up from 1991 to 2019. Data were analyzed between April 2023 and April 2024.

Their analysis was based on databases from two different health studies, one Swedish and one American. Both databases provided genotyping for all cases, as well as health and lifestyle information. The total number of cases was 19,607, and none had PCa at the start of follow-up. Risk level was based on a combination of PRS and family history of cancer. Here is a snapshot:

	Swedish study	U.S. study
Follow-up period	1991-2019	1991-2019
Average length of follow-up	24 years	23 years
Average age at startup	59.0	65.1
Number of high genetic risk cases	7413 (72%)	5773 (62%)

The bad news

The authors found that men in the top 10% of PRSs have a 40-50% chance of developing PCa in their lifetime, and four times the rate of PCa-specific death compared with men in the low PRS range. In all, 444 PCa-specific deaths occurred during the study period; 107 were defined as early death (by age 75) and 337 as late death (after age 75). “Compared with men at lower genetic risk, men at higher genetic risk had a 3-fold increased rate of early and a 2-fold increased rate of late prostate cancer death,” says the study. In short, a high PRS score is not one you want.

The good news

If this sounds like genetic doom, it’s not. Healthy lifestyle can counteract genetic factors. Keep in mind that lifestyle data was available for all cases. The authors took it into account when calculating death rates. “There was a consistent pattern of higher risk among men with an unhealthy lifestyle, and in both cohorts, the highest lifetime risk was observed for men in the PRS 75% to 100% category with an unhealthy lifestyle.” What makes up a healthy lifestyle? The authors combined several factors: healthy weight/BMI, components of healthy diet (e.g. high intake of tomato-based products, fatty fish, and fiber; low intake of processed meat and dairy products) and high physical activity.

Genes are not modifiable, but lifestyle is. This study offers good news for men with high PRSs and a family history of cancer: “Importantly, we estimated that approximately one-third of early prostate cancer deaths among men in this group may be preventable through behaviors associated with a healthy lifestyle.” The bottom line? Regardless of your PRS, embrace a healthy lifestyle now!

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Wang A, Shen J, Rodriguez AA, Saunders EJ et al. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants. Nat Genet. 2023 Dec;55(12):2065-2074. doi: 10.1038/s41588- 023-01534-4.
[ii] Plym A, Zhang Y, Stopsack KH, et al. Early Prostate Cancer Deaths Among Men With Higher vs Lower Genetic Risk. JAMA Netw Open. 2024;7(7):e2420034.