Interleukin-6 promoter variants, prostate cancer risk, and survival

• Published in: The Prostate 2012-12, Vol.72 (16), p.1701-1707
• Main Authors: Tindall, Elizabeth A., Severi, Gianluca, Hoang, Hoa N., Southey, Melissa C., English, Dallas R., Hopper, John L., Giles, Graham G., Hayes, Vanessa M.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alleles; association studies; Biological and medical sciences; Genetic Predisposition to Disease; Genotype; Gynecology. Andrology. Obstetrics; Humans; IL-6; Interleukin-6 - genetics; Male; Male genital diseases; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; promoter variants; Prospective Studies; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - mortality; Risk Factors; survival; Survival Rate; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.22557

BACKGROUND Inflammation has been implicated in prostate cancer (PCa) pathogenesis. Promoter DNA variants responsible for differential expression of key cytokines may therefore influence susceptibility to PCa. METHODS Two interleukin‐6 (IL‐6) promoter variants, −174G>C and −6331T>C, were genotyped for association with PCa risk and survival using the Risk Factors for Prostate Cancer Study (RFPCS, 825 cases and 732 controls) and the Melbourne Collaborative Cohort Study (MCCS, 818 cases and 1,745 controls). Impact of genotypes on IL‐6 transcriptional activity was measured using Low Density Arrays. RESULTS A significant increase in IL‐6 transcriptional activity in malignant compared to benign prostate tissue supports a role for IL‐6 in PCa. The −174G>C variant showed no association with PCa risk, overall survival, or IL‐6 transcriptional activity. The −6331 C‐allele was significantly associated with an increased risk in the RFPCS (OR = 1.29, 95% CI = 1.08–1.54), but not in the MCCS. In the MCCS however, cases presenting with a CC genotype conferred a higher risk of mortality (HR = 2.27, 95% CI = 1.34–3.85), which was maintained although reduced overall in the pooled analysis with RFPCS (HR = 1.68, 95% CI = 1.10–2.54). Furthermore, we associate the minor C‐allele with a significant decrease in IL‐6 transcriptional activity. CONCLUSIONS While our study refutes a role for IL‐6 −174G>C, it is the first to implicate −6331T>C with PCa risk and poor survival. Our observation that −6331T>C has a significant impact on IL‐6 transcriptional activity, calls for further investigations into the role of this variant as a novel PCa biomarker. Prostate 72:1701–1707, 2012. © 2012 Wiley Periodicals, Inc.