Macrophage Inhibitory Cytokine-1 H6D Polymorphism, Prostate Cancer Risk, and Survival

Abstract

Macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor-B superfamily, is important in regulating inflammation. Inflammation of the prostate has been suggested to favor tumor development. A recent study (JNCI 2004(JNCI , 96:1248(JNCI -1254 found marginal evidence of an association between the presence of the mature MIC-1 protein nonsynonymous polymorphism H6D C-to-G (rs1058587) with reduced prostate cancer risk [odds ratio, 0.83; 95% confidence interval (95% CI), 0.69-0.99]. We tested this in a population-based study of 819 cases and 731 controls from Australia and found a similar, yet not significant, odds ratio of 0.85 (95% CI, 0.7-1.04; P = 0.11).We also tested the potential association between the H6D variant and disease-specific survival in 640 cases followed-up for an average of 8.2 years. We found that cases carrying the H6D G allele had an increased risk of death from prostate cancer than cases carrying two copies of the C allele (hazard ratio, 1.72; 95% CI, 1.06-2.78; P = 0.03). Our data suggest that the H6D variant in MIC-1 might play a role in prostate cancer, but it is difficult to explain how a variant can be associated with lower risk of developing prostate cancer but more aggressive growth if cancer develops. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1223 -5)

MIC1 and IL1RN Genetic Variation and Advanced Prostate Cancer Risk

“…For the previously associated H6D polymorphism, the allele frequency among Caucasians (controls/cases, 27.2%/ 26.5%) was similar to the Swedish (controls/cases, 28.8%/ 27.7%) and Australian (controls/cases, 26.5%/24.3%) studies (1,2). Our analysis detected a statistically nonsignificant inverse association between the H6D polymorphism and prostate cancer risk (CG/GG versus CC; OR, 0.85; 95% CI, 0.66-1.09; P = 0.20).…”

“…We did observe a nonsignificant inverse association between the MIC1 H6D polymorphism and prostate cancer as seen in the Australian study (1). To further clarify this effect, we genotyped the H6D polymorphism in a sibling study of 439 prostate cancer cases and 479 unaffected brothers (f90% White, 9% African American, and 1% Asian or Latino; ref.…”

“…Recently, polymorphisms in macrophage inhibitory cytokine-1 (MIC1) and interleukin 1 receptor antagonist (IL1RN) were identified to be associated with prostate cancer risk (1)(2)(3). MIC-1 is a divergent member of the transforming growth factor-h superfamily of cytokines.…”

“…2], whereas an Australian study found this polymorphism associated with a nonsignificant lowered risk of prostate cancer (CG/GG versus CC; OR, 0.85; 95% CI, 0.70-1.04) yet an increased risk of prostate cancer death (CG/GG versus CC; OR, 1.72; 95% CI, 1.06-2.78; ref. 1).…”

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

“…The H6D form of GDF-15 has potential clinical relevance, as several studies indicated better prognosis in prostate cancer (PCa) patients carrying the G allele (H6D protein) than those with wild-type GDF-15. 11,12 According to the Hardy --Weinberg equilibrium, the genotype frequencies in the healthy population were estimated to be 54% for homozygotes containing only histidine (alleles CC), 7% for aspartic acid homozygotes (GG) and 39% for heterozygotes (CG). subsequent proteasomal degradation of the incorrectly folded GDF-15 precursor.…”