Significance of large-scale genetic studies in men of African ancestry

Investigators at USC’s Keck School of Medicine directed the meta-analysis, which discovered nine new genetic variants that boost the risk of prostate cancer in an under researched population, including a genetic risk score connected to aggressive forms of the disease.

Prostate cancer affects Black men more than men of other races. One in every six Black men in the United States will develop prostate cancer during their lifetime, compared to one in every eight men overall. In addition, black men are more than twice as likely to die from the disease.

While nearly 270 genetic variants have been associated with prostate cancer risk in previous studies, scientists have yet to find a proper interpretation for the disproportionate risk between men of African ancestry. So far, genetic research has also failed to anticipate which men are at high risk of developing aggressive prostate cancer versus those who may develop less lethal forms of the disease.

New findings from the largest-ever study of prostate cancer in African American men are now addressing long-unanswered questions. The meta-analysis, conducted by scientists at USC’s Keck School of Medicine, includes data from over 80,000 men from genome-wide association studies.

The research revealed nine new genetic risk factors for prostate cancer, seven of which are found primarily or exclusively in men of African ancestry. For the first time, researchers discovered that genetic differences can help predict which men will develop aggressive prostate cancer. The findings were recently 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. Until now, risk scores haven’t been able to do that,” adds Christopher Haiman, ScD, AFLAC Chair in Cancer Research at the USC Norris Comprehensive Cancer Center and senior author of the study.

These findings can improve polygenic risk scores, which are methods to determine 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 ancestry may aid in the early identification of high-risk patients.

Prostate cancer survival is significantly lower among men diagnosed with aggressive disease. Our findings suggest that these polygenic risk scores could be useful for identifying men who may benefit from earlier and more frequent screenings.”

Fei Chen PhD, Study First Author and Assistant Professor, Clinical Population and Public Health Sciences, Keck School of Medicine

Nine new variants

Investigators pooled data from 10 genome-wide association studies for the meta-analysis, which represented nearly all the available data on genetic risk for prostate cancer in men of African ancestry. This includes data from 19,378 men with prostate cancer and 61,620 healthy controls collected in the United States, Africa, and the Caribbean.

Haiman, Chen, and their co-workers reported nine previously unknown genetic variants that increased the risk of prostate cancer in men of African descent. Seven of those variants are found primarily, if not entirely, in this population, emphasizing the importance of including diverse populations in large-scale genetic studies, according to Chen.

One new variant in the 8q24 region, which has long been known to impact the risk of prostate cancer, 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 discovered some of the same patterns seen in earlier studies, such as the fact that genetic influence plays a larger role in cancer risk for younger men than for older men.

Better screening for prostate cancer

According to Haiman, the newly discovered variants can be integrated into genetic tests that help patients comprehend their cancer risk and decide how early and frequently to get screened.

He and his associates are continuing to study the disease among African American men through the RESPOND initiative, which is supported by the National Institutes of Health and the Prostate Cancer Foundation (PCF), including how social determinants, access to care, and other factors influence prostate cancer recurrence, progression, and survival rates.

One of their long-term objectives is to create a widely available genetic screening test that will assist men of all ages in determining 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,” added Howard R. Soule PhD, PCF Executive Vice President and Chief Science Officer.

Previous research by Haiman’s group identified numerous genetic risk factors for prostate cancer and provided early insights into risk among men of African descent. Proof of risk factors specific to this population emphasizes the significance of collecting 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 concludes.