Prostate cancer is the most common malignancy diagnosed in African American men. Incidence and mortality rates are disproportionately higher among African American men when compared to Caucasian men in the US. The specific factors influencing this disparity remain poorly understood. Although dietary and environmental exposures are among the culprits, evidence exist, which support a role for genetic factors. Candidate gene studies have implicated several genes as being associated with increased prostate cancer risk among African American men. One interesting candidate gene encodes the EphB2 tyrosine kinase gene. The PI and colleagues were the first to report somatic mutations and loss of function of EphB2 in sporadic prostate cancer. Furthermore, we have recently published an association between EphB2 and prostate cancer risk in African Americans. Specifically, we have demonstrated that a common germline nonsense variant in EphB2 confers a three-fold increase in risk in African American men with a positive family history of prostate cancer. Furthermore, this nonsense variant is in admixture disequilibrium in African Americans. Taken together, these and existing data implicating EphB2 in prostate cancer warrant continued investigation. Our central hypothesis is that EphB2 is a genetic risk factor and tumor suppressor gene associated with prostate cancer in African American men. Specifically, we hypothesize that common variants in EphB2 are associated with prostate cancer risk in AA men and that this locus is associated with genomic loss in tumors from AA prostate cancer patients. Furthermore, we hypothesize that a common nonsense variant associated with risk (K1019X) confers a negative functional consequence on the EphB2 protein. To test our hypothesis we are proposing the following specific aims: 1. To test the association between PC risk and germline variants in the EphB2 gene in unselected AA PC cases and controls. 2. To evaluate loss of heterozygosity (LOH) at the EphB2 locus in PC tumors from familial and sporadic AA cases. 3. To perform in vitro functional analysis of the K1019X mutation by introducing a mutated EphB2 construct into EphB2 null DU145 PC cells.
| Robbins, Christiane M; Hooker, Stanley; Kittles, Rick A et al. (2011) EphB2 SNPs and sporadic prostate cancer risk in African American men. PLoS One 6:e19494 |
| Hooker, Stanley; Hernandez, Wenndy; Chen, Hankui et al. (2010) Replication of prostate cancer risk loci on 8q24, 11q13, 17q12, 19q33, and Xp11 in African Americans. Prostate 70:270-5 |
