Genetic-based Risk Assessment for Hepatocellular Carcinoma in Patients with Hepatitis C: Where Do We Stand?

Liver cancer is the second most common cause of cancer-related death, and its incidence is increasing worldwide. Hepatocellular carcinoma (HCC) accounts for 85–90% of cancers arising in the liver. Although many efforts have been made to improve the prognosis of HCC, the mortality from HCC almost equals its incidence, suggesting a dismal prognosis of HCC. The etiologies of HCC are evident, and viral hepatitis contributes the most. Thus, the primary goal in reducing mortality from HCC is the prevention of viral hepatitis. However, for the population already infected with viral hepatitis, the best strategy would be secondary prevention and early detection of HCC with active surveillance. The first essential step in the surveillance strategy is the identification of the population at risk of HCC. The current guidelines simply define high risk as those with cirrhosis from any etiology, and those with chronic hepatitis B virus (HBV) infection irrespective of cirrhosis, based on the estimated HCC risk per year. However, the risk of HCC varies greatly in the target population. Therefore, there is a need for new assessments that can accurately stratify the risk of HCC, enabling more precise surveillance strategies.

Recent advances in sequencing technologies have allowed for the identification of genetic variants, i.e., single nucleotide polymorphisms (SNPs), using genome-wide association studies (GWAS). Unlike the previously-used candidate-gene approach, GWAS enables us to identify genes without any previously suspected role in the pathophysiology of a given disease (Nahon and Zucman-Rossi, 2012). To date, numerous SNPs associated with the development of HCC have been identified in case-control studies (Nahon and Zucman-Rossi, 2012). MHC class I polypeptide-related chain A (MICA) is a membrane protein that acts as a ligand for NKG2D to activate anti-tumor effects through natural killer cells and CD8+ T cells (Bauer et al., 1999). Kumar et al. (2011) demonstrated that MICA polymorphism and serum levels of MICA were associated with a risk for hepatitis C virus (HCV)-induced HCC. In the same group, MICA variants and serum MICA levels were suggested as prognostic biomarkers for HBV-induced HCC, showing a poorer prognosis in the group with high levels of serum MICA (Kumar et al., 2012).

In this issue of EBioMedicine, Huang and colleagues examined four candidate SNPs in a large longitudinal cohort (Huang et al., n.d.). They reported that the MICA A allele and a high serum level of MICA were associated with HCV-related HCC development in cirrhotic patients who did not achieve sustained virological response (SVR), but not in non-cirrhotic patients and/or patients with SVR. The authors suggest that combining the genetic variants of the MICA gene and serum levels of MICA proteins may enhance the predictive power in the high-risk population for HCC. They stressed the impact of the results of their study on the association detected in cirrhotic patients without achieving SVR.

With the introduction of direct acting antivirals (DAAs), it is anticipated that SVR will be achieved in most patients with hepatitis C. However, the availability and affordability of DAAs vary by region, and the role of DAAs in the immune system remains unanswered. Taken together, the authors' conclusion that combining MICA gene variants and serum level of MICA protein may provide insight for closer follow-up strategies and re-treatment priority seems reasonable.

The main contribution of this work lies in the use of longitudinal follow-up data and the adjustment of potential confounders, such as preexisting cirrhosis and viral eradication, in their analysis. Once the association between certain SNPs and the risk of cancers in GWAS has been found in the setting of a case-control study, it should ideally be validated by prospective studies, taking into account non-genetic baseline features (known risk factors) and competing risks (liver disease-related death) (Nahon and Zucman-Rossi, 2012) before being used in clinical practice.

However, care is needed in assessing the utility of genetic tests in real clinical settings, and there are several issues to be considered. Racial differences in the frequency of SNPs have been suggested and should be explored thoroughly. When interpreting associated SNPs, clinical features that might influence the risk for HCC (liver inflammation, fibrosis, or degree of cirrhosis) should be reflected through robust adjustment to avoid misinterpretation of the impact of given SNPs. The role of these genetic variants in the carcinogenic process of HCC and plausible mechanisms should also be elucidated. Lastly, before implementing the use of genetic tests to define population at high-risk for HCC, its cost-effectiveness has to be examined.

Declaration of interests

J Choi has nothing to disclose. Y-SL is an advisory board member of Bayer Healthcare, Bristol-Myers Squibb, and Gilead Sciences, and receives research funding from Bayer Healthcare, Bristol-Myers Squibb, Gilead Sciences, and Novartis. We have no other disclosures to report.