There are currently no biomarkers that predict hepatocellular carcinoma (HCC) risk in patients with hepatitis C virus (HCV)-related cirrhosis. We investigated the relationships among major histocompatibility complex (MHC) class I chain-related gene A (MICA) polymorphisms, plasma levels of soluble MICA (sMICA), and HCC risk in patients with HCV-related HCC. One hundred fifty-four HCV-related HCC patients, 93 HCV-related liver cirrhosis (LC) cases, and 244 healthy controls, all sampled from the native Sicilian population, were genotyped using the KASP™ single-nucleotide polymorphism genotyping method. The MICA rs2596542 polymorphism showed that the G/G genotype was significantly more frequent in HCC than control subjects and LC patients (p < 0.005). For MICA rs2596538 polymorphism, the C allele and C/C genotype were significantly more frequent in HCC than in controls and LC cases (p < 0.005), after controlling for potential confounders. These results demonstrate that MICA rs2596542G/G, and particularly the rs2596538C/C polymorphism, are associated with the risk of developing HCV-related HCC in a Sicilian population sample. Importantly, using a machine learning classifier, we found that "age" and either rs2596542 or rs2596538 were important discriminating factors for patients with LC and HCC. Finally, sMICA levels significantly increased during HCV-related liver disease progression, while a significant relationship between both rs2596542 and rs2596538 genotypes and sMICA plasma levels was identified in patients with LC and HCC. In summary, the MICA rs2596538 and rs2596542 variants warrant further research for their clinical validity and utility in relationship to the risk of developing HCV-related HCC in independent populations.
Keywords: HCV; MICA; genetic association study; hepatocellular carcinoma; liver cirrhosis.