Research led by the University of California, Irvine shows RNA expression differences between prostate tumor and nearby tissue samples that could help explain why Black Americans are more severely affected by this type of cancer than White Americans.
Black Americans are diagnosed with prostate cancer earlier and at a more advanced stage than White Americans and also have a worse prognosis and higher fatality rate from this kind of cancer. While known socio-economic healthcare disparities explain some of these differences, when these are statistically accounted for Black Americans are still more severely affected than White Americans.
“Recent studies indicate that 35% of American prostate cancer patients of African descent assigned to active surveillance gradually undergo aggressive treatments within 5 years due to disease progression, compared to 15% of American patients of European (Caucasian) descent afflicted with the disease,” write the researchers in a paper describing the work published in Oncotarget.
To try and assess whether changes in RNA expression could explain some of the observed population differences, Michael McClelland, a professor at University of California, Irvine, and colleagues collected prostate tumor and tumor-adjacent stroma (representative of overall tumor environment) samples from 15 Black and 30 White individuals with prostate cancer.
The research team found that overall, 932 genes were upregulated and 476 downregulated in Black American compared with White American samples.
When the researchers looked at the top 2500 most significant genes for both the tumor and tumor-adjacent stroma, they found that Black Americans tended to show gene expression indicative of a lower immune response to the cancer in the stroma. They also found gene expression signs indicating that Black individuals were more likely to experience T-cell exhaustion, a common issue when immunotherapy fails, and had higher levels of CTLA4 protein and more CD8 T cells than White patients.
“Interaction of CTLA4 with CD86 inhibits T cell activation and is a key negative regulator of the immune response [to the cancer]… A CTLA4 blockade using ipilimumab and tremelimumab prolongs the antitumor immune responses in melanoma and prostate cancer patients. High expression levels of CTLA4 and CD86 in Black American patients may therefore be indicative of a dysregulated immune response,” write the authors.
Several proteins important for cancer and treatment response were found to be overexpressed in African American individuals including PIK3CA, mTOR and CD53. “The crosstalk between the PIK3 and mTOR pathways can promote prostate cancer progression,” explain the researchers.
“It has been shown that alternative splicing and overexpression of PIK3CD promote tumor aggressiveness and drug resistance in African American prostate cancer patients,” they add.
There is now much more awareness of health-related genetic variation between different population groups and the need to include people from many different ancestries in genetic studies, but despite this 88.5% of all published genome-wide association study participants have European ancestry (according to the GWAS diversity monitor).
Even fewer studies have explored how gene expression data and other ‘omics measures differ between populations, which makes achieving true personalized medicine across all population groups difficult.
The results of the current study show that this kind of analysis is important, particularly for highly variable conditions such as cancer, and should be carried out more regularly and on a greater scale to try and improve clinical diagnostic and prognostic information for all patients.
The authors are now continuing their studies and plan to expand their analysis further to more comprehensively assess how the knowledge of these differences can be used to improve clinical outcomes in these individuals.
