Host genetic predispositions are associated with anti-HCV treatment efficacy, (Huang et al., 2012, 2013a, 2013b) HCV-related liver fibrosis, (Huang et al., 2015a; Urabe et al., 2013) clinical outcome (Noureddin et al., 2013) and HCC (Kumar et al., 2011; Abu Dayyeh et al., 2011; Tanabe et al., 2008; Guyot et al., 2013). However, whether host genetic variants play important roles in HCC development after anti-viral therapy is unclear. By testing the candidate SNPs in a large treatment cohort, we demonstrated that MICA rs2596542 genetic variants predicted HCC occurrence, and the influence was restricted to cirrhotic patients who failed antiviral therapy. Interestingly, we demonstrated that high sMICA was also predictive of HCC occurrence in the population. Most importantly, cirrhotic non-responders were at the highest risk for HCC development, with an annual incidence of 23·5%, if they carried the MICA A allele risk and had high pretreatment sMICA levels.
Preexisting liver cirrhosis is the most critical factor associated with HCC in CHC patients (Lee et al., 2014; Goto & Kato, 2015). Once cirrhosis has evolved, 1 to 4% of patients develop HCC per year (Goto & Kato, 2015). Although successful HCV eradication could reduce the risk of HCC occurrence by 75%, SVR patients remain at risk of HCC development with an average risk of 1·05% per person-year if they have advanced liver disease (Yu et al., 2006a; Morgan et al., 2013). As shown in the current study and other studies, cirrhosis carries a higher hazard risk ratio than failing viral eradication for HCC development in the treatment cohort (Lee et al., 2014; Goto & Kato, 2015). It is therefore imperative to identity the risk of HCC in patients with cirrhotic background with and without SVR.
MICA, a ligand for NKG2D, exerts its anti-tumor effect by activating natural killer benfotiamine and CD8+ T cells. A GWAS demonstrated that patients with HCV-related HCC had a higher rate of the MICA rs2596542 A allele (Kumar et al., 2011). The evidence was based on cross-sectional observations. However, whether genetic predisposition increased the long-term risk of HCC development is unclear. In the current study, we noticed that MICA SNP does not increase the risk of HCC development in patients who had successful viral eradication or mild liver disease. In contrast, among the cirrhotic non-responders who were on the extreme end of liver disease, patients who developed HCC had a significantly higher proportion of the MICA rs2596542 A allele. Carriers of the risk allele had a four-fold risk of HCC development after anti-HCV therapy.
Similar to previous study, we concordantly observed significantly reduced sMICA production in patients with the risk A allele compared with those with GG genotype (Kumar et al., 2011). The pathophysiological mechanism may be due to the potentially low production of membrane-bound MICA with the risk A allele in patients who respond to HCV infection, leading to poor or no activation of immune cells, including NK cells (Kumar et al., 2011; Goto & Kato, 2015). On the other hand, high expression of MICA is associated with a variety of malignancies, including melanoma, breast, colon and hepatocellular cancers (Goto & Kato, 2015; Kumar et al., 2012; Groh et al., 1999, 2002). This result is likely attributed to the fact that highly soluble MICA in the circulation down-regulated NKG2D expression in immune cells and disrupted NKG2D-mediated antitumor immunity. Recently, we also demonstrated that high sMICA levels were also associated with HCV-related HCC recurrence after curative treatment for HCC and antiviral therapy for HCV with and without SVR (Huang et al., 2015b). We observed that cirrhotic non-responders with high sMICA levels (>175ng/mL) had a five-fold risk of HCC development compared with those with low sMICA levels.
Notably in the current study, among cirrhotic non-responders who harbored the low-risk MICA GG genotype, six of seven (85·7%) patients with the high sMICA levels developed HCC during a mean follow-up period of approximately 5years. In contrast, none of the 14 patients with low sMICA levels developed HCC. Subsequently, we identified two risk factors associated with HCC development in cirrhotic non-responders, the carriage of A allele or GG genotype with high sMICA levels. Two-thirds of the cirrhotic non-responders who carried either factor developed HCC with an annual incidence of 23·5%. In contrast, the NPV of HCC development was up to 100% in the clinical setting after approximately 5years of follow-up.