New prostate cancer research from an international team led by the Center for Genetic Epidemiology at the Keck School of Medicine of USC has yielded discoveries that could improve screening and treatment for patients of African ancestry. The scientists identified variants of five genes linked in this population to aggressive disease or to cancer that spreads, or metastasizes, to other organs. The study also found a wide range of risk among participants. By combining data on the five specific genes with other methods of determining risk, the researchers introduced a method that could help identify those most likely to face deadlier forms of the disease.
Screening and treatment advances have greatly improved survival rates for prostate cancer, particularly among those diagnosed in the earliest stages. However, Black patients are still more likely than others to face aggressive forms of the disease and to die from it.
The study, the largest to date looking at rare genetic variants connected to prostate cancer in this population, is a significant step in tackling these disparities. The findings could lead to a more personalized way to identify prostate cancer risk for these patients, which would better inform screening and treatment decisions.
“Our goal is to better understand risk and help reduce the disparity in prostate cancer outcomes,” said Fei Chen, PhD, the study’s first author and an assistant professor of clinical population and public health sciences at the Keck School of Medicine. “We want to identify people who are at high risk of developing aggressive or metastatic prostate cancer. Those patients could then work with their doctors to make decisions about starting screening sooner and testing more frequently in hopes of finding the disease in its early stages.”
The study was published in the journal European Urology.
Five genes with variants linked to aggressive prostate cancer in Black people
The research included data and samples from more than 12,000 Black men from North America and Africa. This included over 7,000 prostate cancer cases and a control group of nearly 5,000. Building on their own advances in identifying genetic risk factors in populations of African descent, as well as previous studies of prostate cancer risk that included people of European, Asian and Hispanic ancestry, the scientists looked at 37 genes linked to prostate cancer.
“Even though high-risk genes have been studied extensively in other populations, they have not been well-defined in populations of African ancestry,” Chen said. “Among those genes, five really stood out in terms of having a strong association with aggressive and metastatic disease.”
The five genes are labeled ATM, BRCA2, CHEK2, HOXB13 and PALB2. Study participants carrying disease-causing variants of these genes were up to six times as likely to develop prostate cancer compared to those without them.
Toward personalized prostate cancer risk assessment
The researchers went a step further to examine how the presence of dangerous genetic variants could inform risk predictions. They started with an existing method developed in research spearheaded by the study’s corresponding author, Christopher Haiman, ScD, holder of the AFLAC Chair in Cancer Research and a professor of population and public health sciences at the Keck School of Medicine of USC.
Called the polygenic risk score, this technique takes into account 451 common gene variants associated with prostate cancer. The team combined that score with information about family history of prostate cancer and the presence or absence of specific variants in any of the five key genes.
This blended method showed promise as a more-refined way of estimating lifetime odds of developing prostate cancer, including risk for aggressive or metastatic disease. Among study participants, the researchers found a very broad range of risk.
Carriers of dangerous genetic variants who also had prostate cancer in their families and polygenic risk scores in the top 10% faced the highest risk of potentially life-threatening disease. Compared to those at average risk, they were seven times more likely to develop prostate cancer, 18 times more likely to have aggressive disease, and 34 times more likely to get metastatic cancer.
“The variability in risk in our study population supports the potential of using a more accurate estimate to develop personalized screening strategies,” Chen said.
What the findings could mean for screening recommendations
Today, the overall National Comprehensive Cancer Network recommendations call for prostate cancer screening to begin at age 45. That age drops to 40 for members of three groups: Black individuals, those with mutations associated with prostate cancer, and those with family histories of prostate cancer.
“Those pieces of information are currently being considered separately,” Chen said. “We demonstrated that combining the information can actually produce a more accurate risk estimate.”
Individualizing risk prediction is expected to benefit those at highest risk for aggressive disease by enabling doctors to detect prostate cancer early, when treatment is more effective. It could also reduce the risk of unnecessary biopsies and of overtreating slow-growing tumors that pose little danger.
“People at low risk for aggressive disease may never have prostate cancer, or they may have a prostate cancer that will never have any great impact on their life,” Chen said. “It may be safe for them to delay screening or screen less frequently. It would prevent the stress and side effects from overdiagnosis of prostate cancer.”
The investigators are continuing the search for genes linked to prostate cancer in Black patients, including connections to aggressive and metastatic disease. The polygenic risk score is already being tested in clinical trials, and future research with humans could validate the inclusion of family history and dangerous gene variants in risk estimations.
About this study
The study’s corresponding author, Christopher Haiman, is also director of the Center for Genetic Epidemiology at the Keck School of Medicine of USC. Other co-authors at USC’s medical school are Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Wei Xiong, Loreall Pooler, Peggy Wan, Susan Gundell, Sue Ann Ingles and David Conti. In all, nearly 80 co-authors contributed to the study, representing more than 30 universities, cancer centers, hospitals, national institutes and laboratories, and other research organizations in the United States, Uganda, Ghana, Senegal, South Africa, Nigeria and France.
The study received funding from the National Cancer Institute [U19CA214253 and U01CA164973], the Prostate Cancer Foundation [20CHAS03] and the American Cancer Society [CRP-24-1191392-01-PROF].
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