The meta-analysis, led by researchers at the Keck School of Medicine of USC, identified nine new genetic variants that increase the risk of prostate cancer in the understudied population, including a genetic risk score linked to aggressive forms of the disease.
By Zara Abrams
Prostate cancer takes a greater toll on Black men than on men of other races. In the United States, one in six Black men will get prostate cancer in their lifetime, compared to one in eight men overall. Black men are also more than twice as likely to die from the disease.
While past studies have identified nearly 270 genetic variants linked to prostate cancer risk, researchers have yet to find a clear explanation for the disproportionate risk among men of African ancestry. Genetic research thus far has also failed to predict which men face a high risk for aggressive prostate cancer, versus those who may get less deadly forms of the disease.
New discoveries from the largest-ever study of prostate cancer in men of African descent are now addressing those long unanswered questions. The meta-analysis, led by researchers at the Keck School of Medicine of USC, includes genome-wide association study data from more than 80,000 men.
The study identified nine new genetic risk factors for prostate cancer, seven of which are found either largely or exclusively in men of African ancestry. For the first time, researchers also found that genetic differences can help determine which men are most likely to develop aggressive prostate cancer. The study was just published in the journal European Urology.
“The ability to differentiate between the risk for aggressive and non-aggressive forms of the disease is of critical importance,” said Christopher Haiman, ScD, AFLAC Chair in Cancer Research at the USC Norris Comprehensive Cancer Center and senior author of the study. “Until now, risk scores haven’t been able to do that.”
These findings can be used to refine polygenic risk scores, tools that assess a person’s risk for a condition based on the combined influence of multiple genetic factors. More accurate polygenic risk scores for men of African descent could help in identifying high-risk patients early on.
“Prostate cancer survival is significantly lower among men diagnosed with aggressive disease,” said Fei Chen, PhD, an assistant professor of clinical population and public health sciences at the Keck School of Medicine and the study’s first author. “Our findings suggest that these polygenic risk scores could be useful for identifying men who may benefit from earlier and more frequent screenings.”
Nine new variants
For the meta-analysis, researchers pooled data from 10 genome-wide association studies—virtually all of the existing data on genetic risk for prostate cancer in men of African ancestry. That includes data collected in the United States, Africa and the Caribbean on 19,378 men with prostate cancer and 61,620 healthy controls.
Haiman, Chen and their colleagues found nine previously undiscovered genetic variants that increased the risk for prostate cancer among men of African descent. Seven of those variants are found primarily—or even exclusively—in this population, which underscores the importance of including diverse populations in large-scale genetic studies, Chen said.
One new variant in the 8q24 region, long known to influence prostate cancer risk, is only found in men of African ancestry. “This particular variant is influencing the risk of aggressive disease in this population,” said Haiman, who also co-leads the USC Norris Cancer Epidemiology Program and is the director of the Center for Genetic Epidemiology at the Keck School of Medicine.
The researchers also detected some of the same patterns seen in previous studies, including that genetic influence plays a bigger role in cancer risk for younger men compared with their older counterparts.
Better screening for prostate cancer
The newly identified variants can be incorporated into genetic tests that help patients understand their cancer risk and decide how early and often to get screened, Haiman said.
Through the RESPOND initiative, funded by the National Institutes of Health and the Prostate Cancer Foundation (PCF), he and his colleagues are continuing to study the disease among African American men, including how social determinants, access to care and other factors affect prostate cancer recurrence, progression and survival rates. One of their long-term goals is to develop a widely available genetic screening test that can help men of all ages assess their risk levels.
“Through the Robert F. Smith-PCF Special Challenge Award for the Smith Polygenic Risk Test, the Prostate Cancer Foundation is proud to invest in the critical work of the RESPOND investigators to understand and address the reasons why African American men disproportionally experience aggressive prostate cancer, and ultimately advance our shared mission to end death and suffering from this disease,” said PCF Executive Vice President and Chief Science Officer Howard R. Soule, PhD.
Earlier research by Haiman’s team identified many genetic risk factors for prostate cancer and offered early insights on risk among men of African ancestry. Evidence of risk factors specific to this population points to the importance of continuing to collect data from diverse groups, including men of African, Asian and Hispanic descent.
“The vast majority of studies to date have been conducted in populations of European ancestry, which creates a huge bias in our understanding of genetic risk for disease,” Haiman said.
About this study
In addition to Haiman and Chen, the study’s other authors are David V. Conti, Burcu F. Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Sue A. Ingles, Suhn K. Rhie, Mariana C. Stern, Susan M. Gundell, Peggy Wan and John D. Carpten of the Departments of Population and Public Health Sciences, Biochemistry and Molecular Medicine, and Translational Genomics, Keck School of Medicine of USC; Ravi K. Madduri and Alex A. Rodriguez of Argonne National Laboratory, Edward J. Saunders, Zsofia Kote-Jarai and Koveela Govindasami of the Institute of Cancer Research, London; Jeannette T. Bensen of the University of North Carolina at Chapel Hill; Rick A. Kittles of City of Hope Comprehensive Cancer Center; Sara S. Strom and Chad D. Huff of the University of Texas M.D. Anderson Cancer Center; Benjamin A. Rybicki and Christine M. Neslund-Dudas of Henry Ford Hospital; Barbara Nemesure and Anselm J. Hennis of Stony Brook University; William B. Isaacs of the James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution; Janet L. Stanford of the Fred Hutchinson Cancer Research Center; Wei Zheng, Melinda C. Aldrich and Todd L. Edwards of Vanderbilt University Medical Center; Maureen Sanderson of Meharry Medical College; Esther M. John and Ann W. Hsing of Stanford University School of Medicine; Jong Y. Park, Thomas A. Sellers and Kosj Yamoah of the Moffitt Cancer Center; Jianfeng Xu of the NorthShore University HealthSystem; Ying Wang and Alpa V. Patel of the American Cancer Society; Sonja I. Berndt, Wei Tang, Michael B. Cook, Stefan Ambs and Stephen J. Chanock of the National Cancer Institute; Edward D. Yeboah and Andrew A. Adjei of the University of Ghana Medical School; Yao Tettey of the University of Ghana and Korle Bu Teaching Hospital; Joseph Lachance of Georgia Institute of Technology; Christopher T. Rentsch of the Yale School of Medicine, the VA Connecticut Healthcare System and the London School of Hygiene & Tropical Medicine; Kelly Cho of Brigham and Women’s Hospital, Harvard Medical School and the VA Boston Healthcare System; Benjamin H. Mcmahon of Los Alamos National Lab; Richard B. Biritwum, Evelyn Tay, Afua Darkwa-Abrahams and James E. Mensah of Korle Bu Teaching Hospital; Ann Truelove and Shelley Niwa of Westat; Adam B. Murphy of Northwestern University; Dana C. Crawford , William S. Bush of the Cleveland Institute for Computational Biology, Case Western Reserve University; Olivier Cussenot of Sorbonne Université and CeRePP, Tenon Hospital, Paris; Gyorgy Petrovics and Jennifer Cullen of Uniformed Services University of the Health Sciences; Anand P. Chokkalingam of the University of California, Berkeley; Phyllis J. Goodman of the Fred Hutchinson Cancer Research Center; Thomas J. Hoffmann of the University of California, San Francisco; Bettina F. Drake of Washington University School of Medicine; Jennifer J. Hu of University of Miami School of Medicine; Jacob M. Keaton of Vanderbilt University Medical Center and the National Human Genome Research Institute, National Institutes of Health; Jacklyn N. Hellwege of Vanderbilt University Medical Center and Vanderbilt Genetics Institute; Peter E. Clark of Atrium Health/Levine Cancer Institute; Mohamed Jalloh, Serigne M. Gueye and Lamine Niang of Hôpital Général Idrissa Pouye, Dakar, Senegal; Olufemi Ogunbiyi, Michael O. Idowu, Olufemi Popoola and Akindele O. Adebiyi of the University of Ibadan and University College Hospital, Ibadan, Nigeria; Oseremen I. Aisuodionoe-Shadrach, Hafees O. Ajibola, Mustapha A. Jamda, Olabode P. Oluwole and Maxwell Nwegbu of the University of Abuja, University of Abuja Teaching Hospital and Cancer Science Center, Abuja, Nigeria; Ben Adusei and Sunny Mante of 37 Military Hospital, Accra, Ghana; Halimatou Diop of Hôpital Aristide Le Dantec, Dakar, Senegal; Stephen K. Van Den Eeden of Kaiser Permanente, Northern California and the University of California, San Francisco; Pascal Blanchet and Laurent Brureau of Univ Antilles, Univ Rennes, Inserm, EHESP, Irset, Pointe-à-Pitre, Guadeloupe, France; Jay H. Fowke of the University of Tennessee Health Science Center; Graham Casey of the University of Virginia; Alexander Lubwama and Stephen Watya of Uro Care, Kampala, Uganda; Ian M. Thompson Jr. of CHRISTUS Santa Rosa Medical Center Hospital; Robin Leach of University of Texas Health Science Center at San Antonio; Douglas F. Easton of Centre for Cancer Genetic Epidemiology, University of Cambridge; Michael H. Preuss and Ruth J. Loos of the Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai; James L. Mohler of the University of North Carolina at Chapel Hill and Roswell Park Cancer Institute; Elizabeth T. Fontham of Louisiana State University Health Sciences Center; Gary J. Smith of Roswell Park Cancer Institute; Jack A. Taylor of the National Institute of Environmental Health Sciences; Shiv Srivastava of Georgetown University Medical Center; Rosaline A. Eeles of the Institute of Cancer Research, London, and Royal Marsden NHS Foundation Trust; Adam S. Kibel of Brigham and Women’s Hospital, Harvard Medical School; Luc Multigner of Univ Rennes, Inserm, EHESP, Irset, Rennes, France; Marie-Elise Parent of Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, Laval, QC, Canada; Florence Menegaux of INSERM, University Paris-Sud, University Paris-Saclay, and Paris-Sud University, Villejuif Cédex, France; Geraldine Cancel-Tassin of Sorbonne Université and CeRePP, Tenon Hospital, Paris, France; Eric A. Klein of Cleveland Clinic Lerner Research Institute; Caroline Andrews of Harvard TH Chan School of Public Health and Division of Population Sciences, Dana Farber Cancer Institute and Glickman Urological & Kidney Institute; Timothy R. Rebbeck of Harvard TH Chan School of Public Health and Division of Population Sciences, Dana Farber Cancer Institute; John S. Witte of Stanford Canter Institute, Stanford University and Kaiser Permanente, Northern California; William J. Blot Vanderbilt University Medical Center and the International Epidemiology Institute; J. Michael Gaziano of Brigham and Women’s Hospital, Harvard Medical School and VA Boston Healthcare System; and Amy C. Justice of Yale School of Medicine and the VA Connecticut Healthcare System.
This work was supported by the National Cancer Institute at the National Institutes of Health [U19CA148537, U19CA214253, R01CA257328, T32CA229110]; the Prostate Cancer Foundation [20CHAS03]; and the Million Veteran Program [MVP017].