Abstract 4001: Unraveling the molecular mechanism of racial disparity in hepatocellular carcinoma (HCC): A link between type I interferon (IFN-I) signaling and HCC disparity

Abstract

Abstract Among HCC patients, there is a statistically significant increase in incidence and mortality as well as a decrease in 5-year survival rates in African-American (hereafter referred to as black) patients compared to non-Hispanic white (hereafter referred to as white) patients. Currently, there is a gap in our understanding of the molecular mechanism underlying this racial disparity. The purpose of this study is to unravel this molecular mechanism. Gene expression profiles were analyzed by RNA-sequencing (RNA-Seq). Canonical pathway analysis of the differentially expressed genes was performed by Ingenuity Pathway Analysis (IPA). Differential expression of the genes was validated by qRT-PCR and immunohistochemistry. The role of the identified genes in regulating proliferation was determined by transient knockdown by siRNA in a patient-derived xenograft (PDX) cell line established from a black HCC patient followed by MTT assay. In TCGA database, RNA-Seq data from 377 HCC patients were available, of which 17 were black and 184 were white. 279 genes were identified, with a p-value<0.01, that are differentially regulated between black and white patients. IPA analysis identified Type I Interferon (IFN-I) signaling as the only pathway that showed statistically significant activation in black patients. RNA-Seq on HCC samples from 14 white and 18 black patients from the tissue bank at VCU Medical Center identified 283 differentially regulated genes and IPA analysis revealed that the only pathway that showed statistically significant activation in black patients is the IFN-I signaling pathway. Activation of the IFN-I signaling pathway in black patients was identified even after correction of the differential gene expression data for HCV status, indicating that the observed findings are independent of HCV infection. Four interferon stimulated genes (ISGs), ISG15, IFI6, MX1 and OAS1, showing significantly increased expression in black HCC patients in both the TCGA database and our own analysis, were chosen for further analysis by qRT-PCR in HCC patient-derived xenografts (PDX) samples from black and white patients, both HCV positive and negative. The levels of the four ISGs were very low in two HCV-negative white HCC PDX lines. In three HCV-negative black HCC PDX lines, their expression levels were significantly and robustly higher. In a HCV-positive black HCC PDX line, their expression was further higher. The results for OAS1, ISG15 and MX1 were validated at the protein level using immunohistochemistry. Transient knock down of IFI6 and ISG15 significantly decreased proliferation of a PDX line established from a black HCC patient. Persistent activation of the IFN-I signaling pathway might be a key determinant of racial disparity in black HCC patients. This pathway might be exploited to develop targeted treatment that work best for black HCC patients. Citation Format: Saranya Chidambaranathan-Reghupaty, Mikhail Dozmorov, Rachel Mendoza, Zhao Lai, Paul B. Fisher, Trevor Reichman, Devanand Sarkar. Unraveling the molecular mechanism of racial disparity in hepatocellular carcinoma (HCC): A link between type I interferon (IFN-I) signaling and HCC disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4001.