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.
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.


CONCLUSIONS
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.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Danyelle A
http://orcid.org/0000-0002-1253-4347
DA
Winchester
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Cathee
C
Till
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Phyllis J
PJ
Goodman
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Catherine M
CM
Tangen
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York.
Regina M
RM
Santella
Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Teresa L
TL
Johnson-Pais
Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Robin J
RJ
Leach
Program for Personalized Cancer Care and Department of Surgery, NorthShore University Health System, Evanston, Illinois.
Jianfeng
http://orcid.org/0000-0002-9419-6627
J
Xu
Program for Personalized Cancer Care and Department of Surgery, NorthShore University Health System, Evanston, Illinois.|Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
S Lilly
SL
Zheng
Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Ian M
IM
Thompson
Department of Pathology, University of Colorado Denver School of Medicine, Aurora, Colorado.
M Scott
MS
Lucia
Moores Cancer Center, University of California San Diego, La Jolla, California.
Scott M
SM
Lippman
Division of Cancer Prevention, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Howard L
HL
Parnes
James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
William B
WB
Isaacs
James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Angelo M
AM
De Marzo
James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, Columbia University, New York, New York.
Charles G
CG
Drake
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.|James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
Elizabeth A
EA
Platz
D000368:Aged; D001706:Biopsy / Q000379:methods; D018120:Finasteride / Q000008:administration & dosage*; D056726:Genetic Association Studies; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide; D011467:Prostate / Q000276:immunology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D064804:Urological Agents / Q000008:administration & dosage
D016209:Interleukin-8; D064804:Urological Agents; D016753:Interleukin-10; D018120:Finasteride
SNPs; finasteride; immune genes; prostate cancer