Association between variants in genes involved in the immune response and prostate cancer risk in men randomized to the finasteride arm in the Prostate Cancer Prevention Trial

Danyelle A. Winchester, Cathee Till, Phyllis J. Goodman, Catherine M. Tangen, Regina M. Santella, Teresa L Johnson-pais, Robin J Leach, Jianfeng Xu, S. Lilly Zheng, Ian M. Thompson, M. Scott Lucia, Scott M. Lippman, Howard L. Parnes, William B. Isaacs, Angelo M. De Marzo, Charles G. Drake, Elizabeth A. Platz

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

BACKGROUND: We 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. RESULTS: Minor 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. CONCLUSION: In 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.

Original languageEnglish (US)
Pages (from-to)908-919
Number of pages12
JournalProstate
Volume77
Issue number8
DOIs
StatePublished - Jun 1 2017

Fingerprint

Finasteride
Prostatic Neoplasms
Odds Ratio
Interleukin-10
Confidence Intervals
Genes
Single Nucleotide Polymorphism
Interleukin-8
Inflammation
Interleukin-4
Interleukin-6
Alleles
Placebos
Interleukin-12
Haplotypes
Interleukin-2
Logistic Models
Biopsy

Keywords

  • finasteride
  • immune genes
  • prostate cancer
  • SNPs

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Association between variants in genes involved in the immune response and prostate cancer risk in men randomized to the finasteride arm in the Prostate Cancer Prevention Trial. / Winchester, Danyelle A.; Till, Cathee; Goodman, Phyllis J.; Tangen, Catherine M.; Santella, Regina M.; Johnson-pais, Teresa L; Leach, Robin J; Xu, Jianfeng; Zheng, S. Lilly; Thompson, Ian M.; Lucia, M. Scott; Lippman, Scott M.; Parnes, Howard L.; Isaacs, William B.; De Marzo, Angelo M.; Drake, Charles G.; Platz, Elizabeth A.

In: Prostate, Vol. 77, No. 8, 01.06.2017, p. 908-919.

Research output: Contribution to journalArticle

Winchester, DA, Till, C, Goodman, PJ, Tangen, CM, Santella, RM, Johnson-pais, TL, Leach, RJ, Xu, J, Zheng, SL, Thompson, IM, Lucia, MS, Lippman, SM, Parnes, HL, Isaacs, WB, De Marzo, AM, Drake, CG & Platz, EA 2017, 'Association between variants in genes involved in the immune response and prostate cancer risk in men randomized to the finasteride arm in the Prostate Cancer Prevention Trial', Prostate, vol. 77, no. 8, pp. 908-919. https://doi.org/10.1002/pros.23346
Winchester, Danyelle A. ; Till, Cathee ; Goodman, Phyllis J. ; Tangen, Catherine M. ; Santella, Regina M. ; Johnson-pais, Teresa L ; Leach, Robin J ; Xu, Jianfeng ; Zheng, S. Lilly ; Thompson, Ian M. ; Lucia, M. Scott ; Lippman, Scott M. ; Parnes, Howard L. ; Isaacs, William B. ; De Marzo, Angelo M. ; Drake, Charles G. ; Platz, Elizabeth A. / Association between variants in genes involved in the immune response and prostate cancer risk in men randomized to the finasteride arm in the Prostate Cancer Prevention Trial. In: Prostate. 2017 ; Vol. 77, No. 8. pp. 908-919.
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abstract = "BACKGROUND: We 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. RESULTS: Minor 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. CONCLUSION: In 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.",
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author = "Winchester, {Danyelle A.} and Cathee Till and Goodman, {Phyllis J.} and Tangen, {Catherine M.} and Santella, {Regina M.} and Johnson-pais, {Teresa L} and Leach, {Robin J} and Jianfeng Xu and Zheng, {S. Lilly} and Thompson, {Ian M.} and Lucia, {M. Scott} and Lippman, {Scott M.} and Parnes, {Howard L.} and Isaacs, {William B.} and {De Marzo}, {Angelo M.} and Drake, {Charles G.} and Platz, {Elizabeth A.}",
year = "2017",
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TY - JOUR

T1 - Association between variants in genes involved in the immune response and prostate cancer risk in men randomized to the finasteride arm in the Prostate Cancer Prevention Trial

AU - Winchester, Danyelle A.

AU - Till, Cathee

AU - Goodman, Phyllis J.

AU - Tangen, Catherine M.

AU - Santella, Regina M.

AU - Johnson-pais, Teresa L

AU - Leach, Robin J

AU - Xu, Jianfeng

AU - Zheng, S. Lilly

AU - Thompson, Ian M.

AU - Lucia, M. Scott

AU - Lippman, Scott M.

AU - Parnes, Howard L.

AU - Isaacs, William B.

AU - De Marzo, Angelo M.

AU - Drake, Charles G.

AU - Platz, Elizabeth A.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - BACKGROUND: We 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. RESULTS: Minor 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. CONCLUSION: In 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.

AB - BACKGROUND: We 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. RESULTS: Minor 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. CONCLUSION: In 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.

KW - finasteride

KW - immune genes

KW - prostate cancer

KW - SNPs

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DO - 10.1002/pros.23346

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SP - 908

EP - 919

JO - Prostate

JF - Prostate

SN - 0270-4137

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