Background: Chronic inflammation as seen with chronic infections, has been proposed as a risk factor for prostate cancer. Numerous studies failed to identify a specific microbial agent associated with prostate cancer risk. We have previously reported that human herpesvirus 8 (HHV-8) is associated with increased prostate cancer risk in Tobago; a population that is 97% of African ancestry. This association was not found in several studies of US men, who were predominately of European American ancestry. It is unclear if the discrepancies between US and Tobago men are due to differences in HHV-8 seroprevalence rates or ancestry-related genetics. Previous studies have reported that the dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene encoding interferon λ4 is more prevalent among individuals of African ancestry and impairs viral clearance. In this study, we investigated whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent.

Methods: We investigated the association of HHV-8 seropositivity with prostate cancer in 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based control men from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT).

Results: HHV-8 seropositivity was higher in cases than controls (OR 1.76; 95%CI: 1.20 - 2.59). The association of HHV-8 seropositivity with prostate cancer was restricted to carriers of the ΔG allele (OR 2.19: 95%CI: 1.38 - 3.48). HHV-8 seropositivity did not associate with prostate cancer among TT/TT genotype carriers (OR 1.03: 95%CI: 0.51 - 2.11). Further stratification by race/ethnicity showed that HHV-8 is associated with prostate cancer exclusively among carriers of the ΔG allele in both European American (OR 2.59; 95%CI: 1.20 - 5.56) and African American men (OR 1.96; 95%CI: 1.08 - 3.56).

Conclusions: HHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant.

Impact: The study establishes IFNL4-ΔG as a candidate prostate cancer risk factor in men with an HHV-8 infection. This gene-environment association of IFNL4-ΔG with prostate cancer should be further evaluated using prospective study designs.

Citation Format: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB162.