Are genetic variations the most important risk factors for development of hepatocellular carcinoma?

Abstract

In patients with type 2 diabetes mellitus (T2DM), cancer is reportedly the second most common cause of mortality, and hepatocellular carcinoma (HCC) is the most frequent type of cancer [1]. However, the pathogenetic factors for HCC development in patients with T2DM remain incompletely understood. Hyperinsulinemia in patients with T2DM is an important pathogenetic factor for the development of cancers, including HCC [2], because insulin promotes carcinogenesis and cell proliferation [2, 3]. Studies have shown that treatment with sulfonylurea and insulin is associated with a significantly increased risk, and that metformin is associated with a significantly decreased risk for the development of HCC in patients with T2DM [4, 5]. It has recently been clarified that an individual’s genetic background is an important risk factor for the development of HCC, even in patients with chronic liver diseases such as chronic hepatitis C (CH-C), chronic hepatitis B (CH-B), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). The single-nucleotide polymorphism (SNP) located near interleukin 28B (IL28B) is reportedly related to development of HCC in patients with CH-C [6]. Genetic variation of IL28B is a strong predictor of virological response to pegylated interferon-a and ribavirin combination therapy for CH-C. Asahina et al. [6] concluded that the cumulative incidence of HCC was significantly higher in the IL28B gene SNP among the patients who did not attain a sustained virologic response on HCV genotype 1. Genetic variation of telomere maintenance genes (TMGs) is closely related to the development of HCC in patients with CH-B [7]. TMGs are essential for maintaining genomic integrity and stability by regulating the length of telomeres and the higher-order structure of protein complexes at the ends of chromosomes [8]. Among five TMGs, the telomerase-associated protein 1 rs1713449 SNP was identified as the most significant risk factor for HCC development and overall survival in patients with CH-B. Moreover, genetic variation of the neurocan (NCAN) gene is a risk factor for HCC in patients with ALD. NCAN is a chondroitin sulfate proteoglycan within the extracellular matrix; it is expressed in neuronal tissue and is involved in brain development and remodeling [9]. Additionally, NCAN is a risk factor for the development of NAFLD, because it is also expressed in the liver [10]. Nischalke et al. [11] reported that the NCAN rs2228603 T-allele is an important risk factor for the development of HCC in patients with ALD. Variation of the PNPLA3 gene (G-allele rs738409) is the most important genetic risk factor for the development and severity of NAFLD according to genome-wide association studies [12, 13]. The G-allele of the PNPLA3 gene is closely associated with Matteoni type 4 nonalcoholic steatohepatitis (NASH) in the Japanese population [14]. With respect to the relationship between HCC and the PNPLA3 gene, the PNPLA3 G-allele is associated with an increased risk of advanced fibrosis and is an independent risk factor for the development of HCC among patients with NASH or ALD-related cirrhosis [15, 16]. Ueyama et al. [17] first reported that genetic variation of PNPLA3 was associated with HCC development in patients with T2DM. Although T2DM is an important risk factor for HCC, the associated genetic background remains unclear. Moreover, it has been considered that HCC This comment refers to the article available at doi:10.1007/s00535015-1116-6.