By Deborah Borfitz
March 2, 2021 | For many kinds of cancer, lifestyle and environmental factors are thought to be important drivers of disease risk. With prostate cancer, it’s a different story. “Aside from having a family history, being of African ancestry, a man, and getting older, there are few clearly established non-genetic risk factors,” says Christopher Haiman, professor of preventive medicine at the Keck School of Medicine of the University of Southern California (USC) and director of the USC Center for Genetic Epidemiology.
Prostate cancer risk is “firmly driven by genetic susceptibility,” Haiman says, which contributes to differences in incidence seen between men of different racial and ethnic groups. Disparities are in fact quite profound—Blacks are at 75% higher risk for prostate cancer and die more than twice as often from the disease compared to whites.
Blacks are, for this reason, a high-priority population for routine prostate-specific antigen (PSA) testing. High PSA levels are associated with prostate cancer but tend to detect slow-growing tumors that wouldn’t necessarily influence a man’s quality of life if they were never detected in the first place. Widespread PSA screening has consequently led to overdiagnosis and unnecessary treatment.
Haiman is part of an international effort to develop a polygenic risk score that can better predict who is at risk of developing prostate cancer. The long-term objective is to identify more aggressive and potentially lethal cases by screening fewer men, thereby improving the cost-benefit ratio of PSA testing, he says.
Multiethnic Approach
The same global research team just completed the largest, most diverse ever prostate cancer genetics study, co-led by the USC Center for Genetic Epidemiology, to better understand why blacks are at higher risk and more likely to die from the disease. Multiple consortiums came together to combine data from most of the genome prostate cancer studies done globally on more than 200,000 men, says Haiman.
Genomic datasets used in the study were from all continents, with the multiethnic meta-analysis including 107,247 men with prostate cancer that were compared to a control group of 127,006 men.
That gave the study, which published in Nature Genetics (DOI: 10.1038/s41588-020-00748-0), unprecedented statistical power to identify risk variants which are important across different populations. Traditionally, variants have largely been discovered in populations of European ancestry and later evaluated in other populations where they may not be as informative in predicting risk, Haiman notes.
The multiethnic approach turned up 86 novel variants, bringing the running total to 269, and in combination they “do a relatively good job of predicting risk across populations,” he says. But, since the largest fraction of samples (79.8%) in the study came from people of European ancestry, the model worked particularly well in that cohort.
Differences emerged when researchers looked at the risk alleles carried by different populations, continues Haiman. Men of African ancestry, for instance, appear to inherit twice as many of the risk variants for prostate cancer compared to men of European ancestry, while men of East Asian ancestry inherited only about three-quarters the risk of their white counterparts.
The genetic risk scoring approach predicts who will develop prostate cancer of any kind, not the more lethal forms, so for risk-stratification purposes it cannot be used to differentiate a man’s risk of developing aggressive versus less aggressive disease, Haiman says.
Additional Studies
In the future, “developing risk scores for specific populations may be optimal,” says Haiman, an effort requiring larger sample sizes in non-white populations to detect variants that are important in specific populations and more reliably estimate effect size of each of the variants for optimizing the risk model. “The models may be different because some of the variants are only found in some populations.” A lot of research is now underway exploring how to refine or better estimate polygenic risk scores for admixed populations, he adds.
On the heels of the Nature Genetics paper, the research team received grant funding to further develop the genetic risk score model by substantially increasing the discovery sample size for minority populations, says Haiman. The new additions include the scanned genomes of men in Africa and the Caribbean as well as the Million Veteran Program of the U.S Department of Veterans Affairs. Additionally, Haiman will be recruiting Latino volunteers in California.
A research initiative backed by the Prostate Cancer Foundation (PCF) and Robert F. Smith (founder, chairman and CEO of Vista Equity Partners) will also help optimize the test for men of African ancestry, Haiman points out. The initiative aims to quadruple the size of his study cohort.
The researchers have plans to conduct large-scale sequencing studies across different populations to explore less common genetic mutations and their contribution to prostate cancer, he adds.
Soon, the team is publishing a study highlighting the inaccuracy of genetic risk scores for breast cancer among African Americans—again stressing the uniqueness of prostate cancer risk being highly determined by genetic factors, says Haiman.
Clinical Utility
The next question to be answered is the clinical utility of the risk score, which will need to be evaluated by a large-scale clinical trial. The hope is to combine PSA screenings with an individual’s risk of developing prostate cancer, says Haiman.
Currently, the methodology finds roughly half of all prostate cancers and half of all men who will develop lethal disease occur in 20% of men in the population. By improving the risk score, it should better define the subset of men where a high proportion of overall and lethal cases occur—information that could be incorporated into decisions about screening, Haiman says.
As discussed in the recently published study, genetic risk scores could in the future fundamentally change PSA screening recommendations that are now based on age, a family history of prostate cancer, and ancestry. Individuals with a high genetic risk score may benefit from earlier and more frequent screening while those at low risk with a borderline screening PSA level might opt not to get a biopsy.
The researchers further found that common genetic variants have a greater impact on prostate cancer risk for early- compared to late-onset disease. This means regular PSA screening may be advantageous before age 55 for a subset of men at high genetic risk, Haiman says. Current recommendations of the U.S. Preventive Task Force don’t address that younger cohort.
Trial particulars are under discussion. One possibility is to enroll men in their 40s and get a baseline PSA and genetic risk score and follow them over time, he says, and many study arms may be required. “Regardless, a long-term initiative is needed because prostate cancer takes a long time to progress.”
Targeting Disparities
As co-senior author on the Nature Genetics paper, Haiman was working on behalf of the Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) consortium, the prostate cancer component of the larger Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative funded by the National Cancer Institute (NCI), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium, led by Rosalind Eelesnd Eeles, professor of oncogenetics at the Institute of Cancer Research (ICR, London), and one of the other co-senior authors on the published study.
The African Ancestry Prostate Cancer GWAS Consortium, which Haiman has led for many years, was among the many groups who participated in the latest genetics study. Others included BioBank Japan (Yokohama) and Kaiser Permanente (Northern California). The groups previously worked together but this was the first time they consolidated their data, says Haiman.
Separately, Haiman leads the RESPOND (Research on Prostate Cancer in African American Men: Defining the Roles of Genetics, Tumor Markers, and Social Stress) initiative that is funded by NCI, the National Institute on Minority Health and Health Disparities, and the PCF. The study aims to recruit 10,000 participants and will generate key biological and non-biological information to help researchers reduce the rate of aggressive prostate cancer among men of African ancestry.
Haiman, who has a background in public health, says a combination of life experiences introduced him to the world of health disparities. He witnessed poverty firsthand as a young boy traveling around Mexico with his family, which sensitized him to global health inequalities. His former department chair at USC (Dr. Donald Ross) and mentor (Dr. Brian Henderson) later challenged and motivated him to home in on the underlying factors contributing to higher prostate cancer risk among African American men, and the clues have pointed strongly to genetics.