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Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.

ABSTRACT: To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer.We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI).The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00-3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48-0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence.Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors.This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis.

SUBMITTER: Dluzniewski PJ

PROVIDER: S-EPMC3467312 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.

Dluzniewski Paul J PJ Wang Ming-Hsi MH Zheng Siqun Lilly SL De Marzo Angelo M AM Drake Charles G CG Fedor Helen L HL Partin Alan W AW Han Misop M Fallin M Daniele MD Xu Jianfeng J Isaacs William B WB Platz Elizabeth A EA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20120802 10

<h4>Background</h4>To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer.<h4>Methods</h4>We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germ ...[more]

PMID: 22859398

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Project description:BackgroundWe previously found that inflammation in benign prostate tissue is associated with an increased odds of prostate cancer, especially higher-grade disease. Since part of this link may be due to genetics, we evaluated the association between single nucleotide polymorphisms (SNPs) in immune response genes and prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial.MethodsWe genotyped 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and seven tagSNPs in IL10 in 881 prostate cancer cases and 848 controls negative for cancer on an end-of-study biopsy. Cases and controls were non-Hispanic white and frequency matched on age and family history. We classified cases as lower (Gleason sum <7; N = 674) and higher (7-10; N = 172) grade, and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history.ResultsThe minor allele (C) of rs3212227 in IL12(p40) was associated with an increased risk of total (log additive: OR = 1.30, 95%CI 1.10-1.53; P-trend = 0.0017) and lower-grade (OR = 1.36, 95%CI 1.15-1.62; P-trend = 0.0004) prostate cancer. The minor allele (A) of rs4073 in IL8 was possibly associated with a decreased risk of higher-grade (OR = 0.81, 95%CI 0.64-1.02; P-trend = 0.07), but not total disease. None of the other candidates was associated with risk. The minor alleles of IL10 tagSNPs rs1800890 (A; OR = 0.87, 95%CI: 0.75-0.99; P-trend = 0.04) and rs3021094 (C; OR = 1.31, 95%CI 1.03-1.66, P-trend = 0.03) were associated with risk; the latter also with lower- (P-trend = 0.04) and possibly higher- (P-trend = 0.06) grade disease. These patterns were similar among men with PSA <2 ng/ml at biopsy.ConclusionVariation in some immune response genes may be associated with prostate cancer risk. These associations were not fully explained by PSA-associated detection bias. Our findings generally support the role of inflammation in the etiology of prostate cancer.

Project description:BackgroundProstate cancer (PCa) is an immune-responsive disease. The current study sought to explore a robust immune-related prognostic gene signature for PCa.MethodsData were retrieved from the tumor Genome Atlas (TCGA) database and GSE46602 database for performing the least absolute shrinkage and selection operator (LASSO) cox regression model analysis. Immune related genes (IRGs) data were retrieved from ImmPort database.ResultsThe weighted gene co-expression network analysis (WGCNA) showed that nine functional modules are correlated with the biochemical recurrence of PCa, including 259 IRGs. Univariate regression analysis and survival analysis identified 35 IRGs correlated with the prognosis of PCa. LASSO Cox regression model analysis was used to construct a risk prognosis model comprising 18 IRGs. Multivariate regression analysis showed that risk score was an independent predictor of the prognosis of PCa. A nomogram comprising a combination of this model and other clinical features showed good prediction accuracy in predicting the prognosis of PCa. Further analysis showed that different risk groups harbored different gene mutations, differential transcriptome expression and different immune infiltration levels. Patients in the high-risk group exhibited more gene mutations compared with those in the low-risk group. Patients in the high-risk groups showed high-frequency mutations in TP53. Immune infiltration analysis showed that M2 macrophages were significantly enriched in the high-risk group implying that it affected prognosis of PCa patients. In addition, immunostimulatory genes were differentially expressed in the high-risk group compared with the low-risk group. BIRC5, as an immune-related gene in the prediction model, was up-regulated in 87.5% of prostate cancer tissues. Knockdown of BIRC5 can inhibit cell proliferation and migration.ConclusionIn summary, a risk prognosis model based on IGRs was developed. A nomogram comprising a combination of this model and other clinical features showed good accuracy in predicting the prognosis of PCa. This model provides a basis for personalized treatment of PCa and can help clinicians in making effective treatment decisions.

Project description:BackgroundWe reported that some, but not all single nucleotide polymorphisms (SNPs) in select immune response genes are associated with prostate cancer, but not individually with the prevalence of intraprostatic inflammation in the Prostate Cancer Prevention Trial (PCPT) placebo arm. Here, we investigated whether these same SNPs are associated with risk of lower- and higher-grade prostate cancer in men randomized to finasteride, and with prevalence of intraprostatic inflammation among controls. Methods A total of 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and 7 tagSNPs in IL10 were genotyped in 625 white prostate cancer cases, and 532 white controls negative for cancer on an end-of-study biopsy nested in the PCPT finasteride arm. We used logistic regression to estimate log-additive odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history.ResultsMinor alleles of rs2243250 (T) in IL4 (OR = 1.46, 95% CI 1.03-2.08, P-trend = 0.03), rs1800896 (G) in IL10 (OR = 0.77, 95% CI 0.61-0.96, P-trend = 0.02), rs2430561 (A) in IFNG (OR = 1.33, 95% CI 1.02-1.74; P-trend = 0.04), rs3747531 (C) in MSR1 (OR = 0.55, 95% CI 0.32-0.95; P-trend = 0.03), and possibly rs4073 (A) in IL8 (OR = 0.81, 95% CI 0.64-1.01, P-trend = 0.06) were associated with higher- (Gleason 7-10; N = 222), but not lower- (Gleason 2-6; N = 380) grade prostate cancer. In men with low PSA (<2 ng/mL), these higher-grade disease associations were attenuated and/or no longer significant, whereas associations with higher-grade disease were apparent for minor alleles of rs1800795 (C: OR = 0.70, 95% CI 0.51-0.94, P-trend = 0.02) and rs1800797 (A: OR = 0.72, 95% CI 0.53-0.98, P-trend = 0.04) in IL6. While some IL10 tagSNPs were associated with lower- and higher-grade prostate cancer, distributions of IL10 haplotypes did not differ, except possibly between higher-grade cases and controls among those with low PSA (P = 0.07). We did not observe an association between the studied SNPs and intraprostatic inflammation in the controls.ConclusionIn the PCPT finasteride arm, variation in genes involved in the immune response, including possibly IL8 and IL10 as in the placebo arm, may be associated with prostate cancer, especially higher-grade disease, but not with intraprostatic inflammation. We cannot rule out PSA-associated detection bias or chance due to multiple testing.

Project description:We previously reported that both intraprostatic inflammation and SNPs in genes involved in the immune response are associated with prostate cancer risk and disease grade. In the present study, we evaluated the association between these SNPs and intraprostatic inflammation in men without a prostate cancer diagnosis.Included in this cross-sectional study were 205 white controls from a case-control study nested in the placebo arm of the Prostate Cancer Prevention Trial. We analyzed inflammation data from the review of H&E-stained prostate tissue sections from biopsies performed per protocol at the end of the trial irrespective of clinical indication, and data for 16 SNPs in key genes involved in the immune response (IL1?, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, TNFA; 7 tagSNPs in IL10). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between carrying at least one minor allele and having at least one biopsy core (of a mean of three reviewed) with inflammation.None of the SNPs evaluated was statistically significantly associated with having at least one core with inflammation. However, possible inverse associations were present for carrying the minor allele of rs2069762 (G) in IL2 (OR?=?0.51, 95%CI 0.25-1.02); carrying two copies of the minor allele of rs1800871 (T) of IL10 (OR?=?0.29, 95%CI 0.08-1.00); and carrying the minor allele of rs486907 (A) in RNASEL (OR?=?0.52, 95%CI 0.26-1.06). After creating a genetic risk score from the three SNPs possibly associated with inflammation, the odds of inflammation increased with increasing number of risk alleles (P-trend?=?0.008).While our findings do not generally support a cross-sectional link between individual SNPs in key genes involved in the immune response and intraprostatic inflammation in men without a prostate cancer diagnosis, they do suggest that some of these variants when in combination may be associated with intraprostatic inflammation in benign tissue.

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Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.

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Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.

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