IFNL4-\u0394G is associated with prostate cancer among men at increased risk of sexually transmitted infections

Tsion Zewdu Minas,Wei Tang,Olusegun O Onabajo,Christopher A Loffredo,Adeola Obajemu,Tiffany H Dorsey,Obadi M Obadi,Bríd M Ryan,Symone V Jordan,Stefan Ambs,Ludmila Prokunina-Olsson,Cheryl J Smith

doi:10.1038/s42003-018-0193-5

Abstract

Sexually transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons. Humans are polymorphic for the germline dinucleotide variant, rs368234815-TT/ΔG, in the IFNL4 gene encoding interferon λ4. Since the IFNL4-ΔG allele has been linked to impaired viral clearance, we hypothesized that potential exposure to sexually transmitted pathogens, as assessed by the number of lifetime sexual partners, may increase prostate cancer risk in an IFNL4-ΔG-dependent manner. Accordingly, we find that men with 10 or more sexual partners and at least one copy of IFNL4-ΔG have a significantly increased risk of prostate cancer while those with the same number of partners but lacking IFNL4-ΔG do not. Moreover, a test for effect modification shows a positive interaction between the number of lifetime partners and IFNL4-ΔG in the development of aggressive prostate cancer. Based on these findings, we conclude that a gene–environment interaction between IFNL4-ΔG and sexual activity may increase the risk of prostate cancer.

Highlights

Transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons
We recently showed that IFNL4-ΔG is closely associated with the occurrence of an interferon signature, termed Interferon-related DNA Damage Resistance Signature (IRDS), in prostate tumors of AfricanAmerican patients with decreased overall survival in this patient group[25]
We identified a gene–environment interaction between IFNL4-ΔG and an increased likelihood of exposure to sexually transmitted infections (STI) resulting in the development of aggressive prostate cancer, suggesting a yet unidentified relationship between an infectious agent and prostate cancer in men with IFNL4-ΔG

Summary

Introduction

Transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons. One of the host factors of importance for innate immune response to STI could be a germline dinucleotide polymorphism, rs368234815 (TT or ΔG alleles), in the IFNL4 gene that encodes IFN-λ4, a type-III interferon[16,17]. IFN-λ4 is an antiviral cytokine and a potent inducer of the JAK-STAT pathway, individuals carrying the IFNL4-ΔG allele have impaired ability to clear certain viral infections such as hepatitis C virus (HCV)[16,18,19], cytomegalovirus[20,21], coronavirus[22,23], and possibly HIV24 This effect has been attributed to increased induction of negative regulators of interferon signaling by IFN-λ4 that could affect the function of other interferons[16,17]. We identified a gene–environment interaction between IFNL4-ΔG and an increased likelihood of exposure to STI resulting in the development of aggressive prostate cancer, suggesting a yet unidentified relationship between an infectious agent and prostate cancer in men with IFNL4-ΔG

Methods

Results

Conclusion