Prostate-Specific Membrane Antigen-Dependent Health Disparities in Prostate Cancer
Abstract
Prostate cancer (PC) is an extremely common cancer in men in the United States. It is predicted that nearly 174,650 men will be diagnosed with PC in 2019, with approximately 31,620 disease-related deaths. PC rates vary markedly among individual race and ethnic groups, and African American (AA) men are affected at a disproportionally increased rate. PC is also more aggressive earlier in AA men and as a result, AA men are more likely to have an advanced stage of disease than men of European decent (EUR) at a similar age. In military personnel, PC is the most frequent cancer diagnosis reported by the U.S. Department of Veterans Affairs, again with AA men displaying strikingly more cases. Even when socioeconomic disparities and inequitable access to opportunities and resources (such as work, wealth, income, education, housing, and overall standard of living, as well as barriers to high-quality cancer prevention, early detection, and treatment information and services) are taken into account, the disparity still persists, hinting that there is a genetic factor that could be responsible for this disparity. Currently, patients with advanced PC receive chemotherapy combined with drugs to slow tumor growth. Although this is initially effective and improves survival, most patients develop untreatable, drug-resistant tumors. Serum prostate-specific antigen (PSA) is the clinical standard for early detection of PC and can aid in treatment decision-making between the patient and their health care provider. However, PSA is burdened by low sensitivity and specificity. Despite being at a higher risk of disease, AA men are less likely than EUR men to be provided the option of having a PSA test and to be told of the uncertainty of the benefit of testing. These are major obstacles to designing effective PC screening and treatment strategies. Therefore, investigation into these molecular and genetic mechanisms not only has the capacity to improve the outcomes of all men with lethal PC by identifying higher-risk segments of the population, but also has the potential to enhance the understanding of the molecular differences observed in cancer incidence, prevalence, morbidity, and mortality rates among AA men. Levels of a protein called Prostate-specific membrane antigen (PSMA) increase along with PC tumor progression, and it has been used successfully in the clinic as a marker of PC. Additionally, in advanced PC, PSMA supports tumor development by producing substances required for cell growth. Additionally, our group recently published data from our laboratory that shows that increases in PSMA result in changes in PC cells that allow them to be more resistant to cell death, thus encouraging PC tumor growth. Small differences in the genetic makeup of individuals, called single nucleotide polymorphisms (SNPs), can increase or decrease the ability of certain genes to function and can be found commonly in groups of patients with the same disease. Although over a dozen SNPs have been highly linked with PC, individually these SNPs do not account for a large fraction of genetic PC risk. It is possible that a combination of SNPs might act together to contribute to PC progression. Interestingly, a number of moderately associated SNPs have been identified in genes that may positively and/or negatively affect the levels or function of PSMA and could impact the production of the proteins that help tumors grow. Intriguingly, elevated levels of these proteins contribute to PC aggressiveness, particularly in AA men. In preliminary studies, we found that, in 16 PC genetic studies, mutations are present in one or more of the pathways that PSMA uses to produce substances required for cell growth, and patients harboring multiple mutations in these genes have a poor outcome. Additionally, we have identified a panel of potentially harmful coding SNPs that is in higher abundance in PC patients and differs in EUR versus AA PC patients, suggesting
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010202
Entities
People
- Leslie Caromile
Organizations
- United States Army
- University of Connecticut Health Center