Rational and Objective: Prostate cancer (CaP), similarly to other common malignancies, displays health disparities reflecting differences in cancer incidence, mortality, and prevalence among different populations. It has been known for over 30 years that African Americans (AA) have a higher incidence of CaP and a worse prognosis when compared to Caucasian Americans (CA). In addition to examining socioeconomic factors that may be contributing to these findings, researchers have also been searching for inherited and somatic genetic differences that may help to explain the increased risk of CaP and worse prognosis in men of African ancestry.
One somatic genetic event, the oncogenic activation of ERG resulting from prevalent gene fusions, is present in two-thirds of CaP patients in Western countries. We and others noted a lower frequency of ERG-positive CaP type in AA compared to CA CaP patients. This observation has now been validated in a rigorously designed study from our Center. The significantly lower frequency of ERG oncoprotein in AA patients emerges as a major difference of a somatic mutation between AA and CA CaP.
The surprisingly increased association of ERG negative index tumor type with higher Gleason grade CaP in AA patients suggests that ERG typing of CaP may have an unexplored prognostic value in AA CaP patients. The primary objective of this grant proposal is to identify molecular determinants (somatic mutations and inherited genetic variations) of aggressive CaP in AA patients by ERG-based stratification of CaP.
Applicability of the Research: It is hypothesized that ERG oncoprotein status of AA and CA patients reflects the underlying biological or genetic differences in CaP incidence and outcomes observed across race. Typing tumors for ERG protein opens the possibility of a rapid and targeted search for inherited genetic variations (SNPs), which may be determinants of the somatically acquired ERG-positive CaP type in CA and AA patients.
Tests for inherited genetic variations (including SNPs) are non-invasive, inexpensive, rapid procedures that can be done from a small amount of blood sample. As these variations are inherited, they can be tested for very early. An early positive test will provide an opportunity to make adjustments in diet and lifestyle, as well as a potential reason for earlier screening in AA men carrying these risk alleles.
Contributions to Advance Health Disparity Research: To date, the majority of genetic association studies have been performed in men of European ancestry. The proposed study focuses on both inherited genetic polymorphism and somatic mutations in AA CaP patients. Our unique patient cohort, treated by radical prostatectomy at the Walter Reed National Military Medical Center, is within the equal access Department of Defense healthcare beneficiary system. We reasoned that in this system socio-economic factors influencing disparity are less pronounced leaving genetic factors easier to pinpoint.
We propose to incorporate significant molecular findings (ERG typing, somatic mutations/markers in ERG-negative CaP, ERG type associated SNPs) into traditional pathological and clinical nomograms. The long-term contribution of this study will be to ultimately decrease CaP disparity by the use of these new nomograms specifically designed for AA patients.