Abstract
The EphB2 gene has been implicated as a tumor suppressor gene somatically altered in both prostate cancer (PC) and colorectal cancer. We have previously shown an association between an EphB2 germline nonsense variant and risk of familial prostate cancer among African American Men (AAM). Here we set out to test the hypothesis that common variation within the EphB2 locus is associated with increased risk of sporadic PC in AAM. We genotyped a set of 341 single nucleotide polymorphisms (SNPs) encompassing the EphB2 locus, including known and novel coding and noncoding variants, in 490 AA sporadic PC cases and 567 matched controls. Single marker-based logistical regression analyses revealed seven EphB2 SNPs showing statistically significant association with prostate cancer risk in our population. The most significant association was achieved for a novel synonymous coding SNP, TGen-624, (Odds Ratio (OR) = 0.22; 95% Confidence Interval (CI) 0.08–0.66, p = 1×10−5). Two other SNPs also show significant associations toward a protective effect rs10465543 and rs12090415 (p = 1×10−4), OR = 0.49 and 0.7, respectively. Two additional SNPs revealed trends towards an increase in risk of prostate cancer, rs4612601 and rs4263970 (p = 0.001), OR = 1.35 and 1.31, respectively. Furthermore, haplotype analysis revealed low levels of linkage disequilibrium within the region, with two blocks being associated with prostate cancer risk among our population. These data suggest that genetic variation at the EphB2 locus may increase risk of sporadic PC among AAM.
Highlights
Prostate cancer (PC) remains the most common male specific malignancy diagnosed in the U.S In 2010 alone about 217,730 new cases of prostate cancer accounted for 28% of diagnoses for the ten leading cancer types
An independent study looking at 72 probands from African American hereditary prostate cancer families identified 10 sequence variants in the EphB2 gene [18]
We undertook a study to determine if genetic variation at the EphB2 locus is associated with risk of sporadic prostate cancer among African American men
Summary
Prostate cancer (PC) remains the most common male specific malignancy diagnosed in the U.S In 2010 alone about 217,730 new cases of prostate cancer accounted for 28% of diagnoses for the ten leading cancer types. An estimated 32,050 deaths are attributed to this disease annually [1] Many risk factors such as diet, lifestyle, hormones, age, and race have been implicated as contributing to the risk of prostate cancer; family history is the single most significant and reproducible risk factor known, where men with two or three first degree relatives with prostate cancer had a five and 11-fold increased risk of developing prostate cancer, respectively [2,3]. The 2002–2006 incidence rate of prostate cancer in the U.S per 100,000 men was 231.9 in AAM versus 146.3 in European American Men (EAM) [1] This disparity is seen even more drastically when looking at the death rates amongst these two groups with AAM having a greater than two-fold higher (56.3 per 100,000) prostate cancer death rate compared to EAM (23.6 per 100,000) during this same time-frame [1]. Compelling evidence shows strong genetic association between prostate cancer risk and genetic markers at 8q24, where several of the risk alleles have minor allele frequencies that are higher within populations of recent West African decent, suggesting a role in the increased incidence of prostate cancer in AAM [5,6,7,8,9,10]
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