Abstract B051: IFNL4-deltaG allele is associated with an interferon signature in tumors and survival of African-American men with prostate cancer

Abstract

Abstract 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 λ4 (IFNL4) gene. Experimental Design: We analyzed gene expression in prostate tissue datasets and performed IFNL4 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-ΔG) that controls production of IFN-λ4 protein, a type-III interferon, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-ΔG allele was significantly associated with IRDS in prostate tumors and overall survival of African-American patients. Moreover, IFNL4 overexpression induced IRDS-like signatures in three human prostate cancer cell lines. Conclusions: Tumor interferon signaling has recently been shown to modulate response and resistance to immune checkpoint blockade. Here, we describe a distinct and biologically relevant interferon signature, IRDS, in prostate tumors that has a high prevalence in African-American patients. Our observations indicate that IRDS and IFNL4 rs368234815-ΔG may have a function in the tumor biology and survival of African-American patients, and influence immune therapy outcomes, which should be examined in future studies. Citation Format: Wei Tang, Tiffany Wallace, Ming Yi, Cristina Magi-Galluzzi, Tiffany Dorsey, Olusegun Onabajo, Adeola Obajemu, Symone Jordan, Christopher Loffredo, Robert Stephens, Robert Silverman, George Stark, Eric Klein, Ludmila Prokunina-Olsson, Stefan Ambs. IFNL4-deltaG allele is associated with an interferon signature in tumors and survival of African-American men with prostate cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B051.