IFNL4-ΔG predisposes to aggressive prostate cancer among men at increased risk of sexually transmitted infections

Authors

• TZ MINAS
• W TANG
• CJ SMITH
• TH DORSEY
• SV JORDAN
• OM OBADI
• L PROKUNINA-OLSSON
• BM RYAN
• CA LOFFREDO
• S AMBS

Abstract

Introduction: Sexually transmitted infections affect epithelium of urogenital tract and may reach the prostate. First response to exogenous pathogens is controlled by the innate immune response, including interferons. Humans are polymorphic for the dinucleotide variant rs368234815-TT/ΔG in the IFNL4 gene that encodes IFN-λ4, a type-III interferon. Since IFNL4-ΔG has been linked to impaired viral clearance, we hypothesized that potential exposure to sexually transmitted pathogens, as assessed by the number of sexual partners, may increase prostate cancer risk in an IFNL4-ΔG-dependent manner. Methods: Multivariable logistic regression was used to examine the association between the number of sexual partners, rs368234815 genotypes, and prostate cancer risk in the NCI-Maryland Prostate Cancer Case-Control Study, which includes 976 prostate cancer cases and 1,034 population controls. Results: Men who had 10 or more sexual partners in their twenties and thirties had a significantly increased risk of developing prostate cancer compared to men with 0-1 partners. This risk was modified by IFNL4-ΔG such that men with 10 or more partners and at least one copy of IFNL4-ΔG allele had a significantly increased risk of prostate cancer compared to those with the same number of partners but lacking IFNL4-ΔG. The risk of aggressive prostate cancer was significantly modified by an interaction between the numbers of sexual partners and IFNL4-ΔG alleles. Conclusions: A gene-environment interaction between the IFNL4-ΔG allele responsible for production of IFN-λ4, and exposure to sexually transmitted infections, contributes to increased risk of aggressive prostate cancer. As the frequency of the ΔG allele is higher among men of African descent, our data suggest that this allele could explain some of the observed prostate cancer health disparity.

Scientific Focus Area: Health Disparities

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