IFNL4-{Delta}G allele is associated with an interferon signature in tumors and survival of African-American men with prostate cancer

Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the interferon 4 (IFNL4) gene. Experimental Design: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells. Results: We found that a distinct interferon signature that is analogous to the previously described "Interferon-related DNA Damage Resistance Signature" (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of African-American than European-American men. Furthermore, analysis in The Cancer Genome Atlas (TCGA) showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815-G) that controls production of IFN-4 a type-III interferon, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-G allele was significantly associated with IRDS in prostate tumors and overall survival of African-American patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines. Conclusions: Our study links a germline variant that controls production of IFN-4 to the occurrence of a clinically relevant interferon signature in prostate tumors that may predominantly affect men of African ancestry.

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