Patrick R. Shea

RNASEL and RNASEL‐inhibitor variation and prostate cancer risk in Afro‐Caribbeans

Afro‐Caribbeans from Tobago are at high risk of developing prostate cancer. This elevated risk of prostate cancer is shared by populations of African ancestry living in diverse environments in the Western hemisphere. Variation in the ribonuclease L (RNASEL) gene has recently been reported to be associated with an increased risk of prostate cancer. However, whether RNASEL variation contributes to the increased risk of prostate cancer observed in populations of African ancestry remains unclear.

ELAC2 and prostate cancer risk in Afro-Caribbeans of Tobago.

Abstract. To test the hypothesis that variation in the putative prostate cancer susceptibility gene ELAC2 contributes to the elevated risk of prostate cancer in Afro-Caribbean males from Tobago, we genotyped the S217L and A514T polymorphisms, previously reported to be associated with prostate cancer risk in a large sample of cases and controls. The frequency of the high-risk Leu allele at the S217L site was the same in cases and controls. Both cases and controls were homozygous for the low-risk Ala allele at the A514T site. In addition, we sequenced the exons and 3′- and 5′-flanking regions of ELAC2 in 24 individuals with histologically confirmed prostate cancer. We identified 17 new single nucleotide polymorphisms. An A(–1196)T polymorphism, which alters a predicted TATA box consensus sequence, was tested in cases and controls, and no significant difference in allele or genotype frequencies was observed. The absence of ELAC2 mutations and lack of association between polymorphisms in ELAC2 and prostate cancer in cases and controls leads us to conclude that ELAC2 does not contribute significantly to the elevated prevalence of prostate cancer in Afro-Caribbean males of Tobago.

Abstract 5726: Association between human herpesvirus 8 infection, inflammation and a polymorphism in the IL-6 signaling receptor in increased prostate cancer risk among men of African descent

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Prostate cancer is more prevalent among African Americans than Caucasians and this increased risk among men of African descent is not limited to the United States, suggesting a role for genetic or shared lifestyle factors. In our previous population-based study on the Caribbean island of Tobago, the prevalence of screening-detected prostate cancer was 3-fold higher compared to similarly screened US Caucasian men. The island of Tobago is 95% of African descent and represents a homogeneous population for studying genetic factors associated with disease. Inflammation has also been suggested as a co-factor for increased prostate cancer risk, and studies have demonstrated positive correlations with prostatitis and sexually transmitted diseases. We have previously reported an increased seroprevalence to human herpesvirus 8 (HHV-8) among Tobago men with prostate cancer (n=138) compared to Tobago age-matched controls (n=140; OR 2.24, 95% C.I. 1.29-3.90). In the current study we have expanded our earlier findings demonstrating an association between HHV-8 infection, inflammation and a polymorphism in the IL-6 signaling receptor gp130 in prostate cancer risk among men of African descent. Methods: Biopsies (n=19) and prostectomies (n=20) of Tobago men with histologically confirmed prostate cancer were analyzed by immunohistochemistry for expression of the HHV-8 proteins LANA-1, K8.1 or vIL-6 and the presence of B cells and macrophages. SNP analysis for the G148R polymorphism was performed on Tobago (n=1,217) and U.S. (n=149) men. Lymphoblastoid cell lines (LCLs) were constructed from Tobago men representing the three possible genotypes of the gp130 polymorphism (G148R; G/G, G/R and R/R). Growth curve analyses were performed on the LCLs grown in the absence or presence of 25ng/ml IL-6. Results: HHV-8 proteins were expressed in 75% of the prostate biopsies and 100% of the prostectomies of seropositive men. Viral protein expression was more prevalent in sections containing cancer compared to cancer free sections (p=0.001). Seropositive men who were homozygous for the R/R gp130 allele were significantly more likely to have prostate cancer than seronegative men who were homozygous for the G/G allele (n=400; OR 3.1, 95% C.I. 1.18-8.11). Increased inflammation (macrophage infiltration) in non-cancerous sections was associated with gp130 status (p=0.023). LCLs homozygous for the high risk gp130 allele demonstrated a 250% increase in growth compared to the homozygous low risk. Summary: Taken together, our results support the hypothesis that HHV-8 establishes a chronic infection producing chronic inflammation which, in association with a polymorphism in the IL-6 signaling receptor, results in increased prostate cancer risk among men of African descent in Tobago. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5726.