Genetic Ancestry and Prostate Cancer: Personalizing Early Detection and Treatment

Ancestry-informed biology and precision treatment are helping to change the game for patients with prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in men, but the experience is not the same for everyone. In the United States, African American men are far more likely to be diagnosed with prostate cancer and twice as likely to die from the disease compared with white men. Globally, men of African descent, including those in sub‑Saharan Africa, often develop prostate cancer earlier and with more aggressive tumors.

For nearly two decades, the American Association for Cancer Research (AACR) has put a spotlight on research examining disparities like those seen in prostate cancer at its celebrated AACR Conference on the Science of Cancer Health Disparities. At this year’s conference, researchers shared how ancestry, where you live, and even how your immune system behaves can affect how prostate cancer progresses and which diagnostic tests and treatments work best.

Among the researchers presenting at the conference were Clayton Yates, MS, PhD, professor at the Johns Hopkins School of Medicine; Melissa Davis, PhD, professor at the Morehouse School of Medicine; and Dayanne Rodriguez, a PhD candidate at the National Cancer Institute of Colombia. Together, their work points to a future where screening and treatment are more accurate and precise for everyone.

Identifying the Ties Between Ancestry and Prostate Cancer

“Our understanding of the association of ancestry and prostate cancer risk and outcomes has evolved over the years,” explained Dr. Yates, who also serves as coprincipal investigator of the Prostate Cancer Transatlantic Consortium (CaPTC). “What we’re starting to learn is that there are ancestry-associated markers that are driving and causing this disease to be more aggressive.” 

Dr. Yates’ research is examining how there are certain immune and inflammatory pathways associated with prostate cancer in patients with a higher proportion of African ancestry. Dr. Yates singled out two markers: PTN, which is a gene that promotes the expression of VGEF, a known tumor biomarker; and TNF signaling, which is a pathway associated with inflammation and controls cell proliferation and cell death. Together, Dr. Yates explained, they can flag a “suppressed” immune microenvironment, where the body’s defenses are muted, giving the tumor room to grow.

Rodriguez, who presented a poster at the conference, explained the need to also identify markers that work better in admixed populations, which consist of individuals with multiple genetic ancestries. This is the case in Rodriguez’s home country of Colombia, where the population represents an admix of European, Native American, and African genetic ancestries.  

“Prostate cancer is a principal cause of death among men in our country, and our admixed population leads to a lot of heterogeneity and biological tumor difference that can make it difficult to diagnose this disease at an early stage,” said Rodriguez.

Through her research, Rodriguez has found that some markers for prostate cancer in Colombian men behave differently depending on ancestry. This affects the quality and accuracy of existing screening techniques, because PSA and PCA3—widely used tests for detecting prostate cancer— often perform better in men of European ancestry, she noted. But Rodriguez identified 29 new prostate cancer biomarkers in Colombian men. Of these, nine biomarkers were found to be associated with European ancestry: ACY1, ALCAM, APOE, EEF1A2, FASN, GOLM1, HPN, PCA3, and PKP3. Additionally, three genes were detected in association with African ancestry. However, these require further validation as they are related to oncogenic processes, but it is still unclear whether ancestry may be modulating this response. Once validated, the next step would be to see if these biomarkers could be included along with PSA and PCA3 screening to improve early detection of prostate cancer in her country.

How Ancestry Affects Prostate Cancer Treatment Outcomes

Dr. Yates emphasized that ancestry doesn’t just influence risk; it can also shape how patients respond to treatment. While most immunotherapy trials for prostate cancer have shown limited success overall, recent studies led by Oliver Sartor, MD, director of the Transformational Prostate Cancer Research Center at the East Jefferson Hospital Cancer Center, and Daniel George, MD, professor at Duke University, revealed that African American men respond nearly twice as well to sipuleucel‑T (Provenge), an immunotherapy approved by the U.S. Food and Drug Administration, than men of European ancestry. These findings underscore the biological differences driving treatment outcomes and highlight why ancestry-informed research is critical.

“By understanding the biology, we can tailor and precision-target individuals with the right therapeutic,” Dr. Yates explained.  

The early results from his own research on PTN and TNF signaling have found that these markers better predicted outcomes in African American men than in men of European ancestry. If validated in larger groups, such assays could help doctors identify who needs aggressive treatment sooner, Dr. Yates noted. 

Drs. Davis and Yates also pointed out that since treatment outcomes may differ based on ancestry, clinical trials should be designed with this in mind. For example, Drs. Davis and Yates, along with other researchers, are studying how the differences in vitamin D deficiency between African American and European men may impact cell growth and immune response in prostate cancer patients.

Their research shows that the vitamin D receptor function is most dynamic in African American prostate cells but becomes distorted in cancerous states, partly due to reduced expression of BAZ1A, a chromatin remodeler. This means that by altering the structure of chromatin, BAZ1A controls the accessibility of DNA to other proteins through nucleosome positioning, which is vital for fundamental cellular processes like DNA replication, repair, and transcription. They discovered that vitamin D supplementation elicited a strong genomic response in tumors from African American patients, with genes linked to inflammation, circadian rhythm, and prostate lineage regulation showing significant activation, whereas tumors from European American patients exhibited virtually no response. This means that ancestry-informed clinical trials are needed to understand the full effect of therapeutic plans like vitamin D supplementation.

Greater Context—How Genomics and the Exposome Influence Prostate Cancer

Dr. Davis emphasized that disparities aren’t driven by biology alone. Factors like diet, chronic stress, pollution exposure, and other health conditions (comorbidities like diabetes or hypertension), collectively called the exposome, can all shape how prostate cancer begins and evolves. She explained that in her work leading team SAMBAI (Societal, Ancestry, Molecular, and Biological Analyses of Inequalities)— a research project that focuses on breast, prostate, and pancreatic cancer disparities in the African diaspora—they are examining how integrating exposome data with genomic profiles could uncover hidden drivers of aggressive prostate cancer. For example, chronic inflammation linked to environmental stressors may amplify tumor-promoting pathways in certain populations. This systems-level approach could lead to interventions that target not just the tumor, but the conditions that fuel it.

That is why Dr. Davis said data are needed across all facets—genomics, exposomics, social determinants of health, psychosocial health, and more—to best understand what components are the most influential in driving the etiology of these tumors and to identify ways to treat them for a particular population of men. To analyze all this data, she said that artificial intelligence (AI) will be critical.

“We’re talking about tens of thousands of individuals,” said Dr. Davis. “That’s going to equate to billions of data points across a diverse platform of multidisciplinary data. The computationally intense capabilities of AI will be able to look for patterns in that data that could lead to targeted therapies to help ameliorate the disparities.”

Adding to this, Dr. Yates explained that his team is working on AI tools not only to predict tumor response but also understand how the cell shape and morphology is connected to genetics, enabling a holistic perspective of a patient’s status.

“Ancestry is one component, but we use that to dichotomize a complex situation and tailor treatment to each individual,” he said. “In some cases, we may identify nonancestry-related risk factors that can be targeted through nutrition changes in the diet as well as societal- or policy-driven changes that could improve access to care.” 

Together, these findings underscore a critical message: Prostate cancer disparities are the result of a complex interplay of ancestry, environment, and biology. Future screening tools may incorporate ancestry-specific biomarkers and immune profiles while using AI tools to process the information. The ideas of researchers like Dr. Davis, Dr. Yates, and Rodriguez help paint a picture of a world where therapies could be tailored, not just to the tumor, but to the patient’s genomic and environmental context.