Are genetic variations the most important risk factors for development of hepatocellular carcinoma?
Are genetic variations the most important risk factors for development of hepatocellular carcinoma?
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DOI：
10.1007/s00535-015-1130-8
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发表时间：
2016-04
影响因子：
6.3
通讯作者：
M. Ono;T. Saibara
中科院分区：
文献类型：
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作者：
M. Ono;T. Saibara
据报道，在2型糖尿病（T2 DM）患者中，癌症是第二大常见死亡原因，肝细胞癌（HCC）是最常见的癌症类型[1]。然而，T2 DM患者发生HCC的致病因素仍不完全清楚。T2 DM患者的高胰岛素血症是癌症（包括HCC）发展的重要致病因素[2]，因为胰岛素促进致癌作用和细胞增殖[2，3]。研究表明，磺脲类药物和胰岛素治疗与T2 DM患者发生HCC的风险显著增加相关，二甲双胍与T2 DM患者发生HCC的风险显著降低相关[4，5]。最近已经阐明，个体的遗传背景是HCC发展的重要危险因素，甚至在患有慢性肝病如慢性丙型肝炎（CH-C）、慢性B肝炎（CH-B）、酒精性肝病（ALD）和非酒精性脂肪性肝病（NAFLD）的患者中也是如此。据报道，位于白细胞介素28 B（IL 28 B）附近的单核苷酸多态性（SNP）与CH-C患者的HCC发生相关[6]。IL 28 B的遗传变异是对聚乙二醇干扰素-o和利巴韦林联合治疗CH-C的病毒学应答的强预测因子。Asahina等人[6]结论是，在HCV基因型1没有获得持续病毒学应答的患者中，IL 28 B基因SNP的HCC累积发病率显著较高。端粒维持基因（TMG）的遗传变异与CH-B患者HCC的发生密切相关[7]。TMG通过调节端粒的长度和染色体末端蛋白质复合物的高阶结构，对维持基因组的完整性和稳定性至关重要[8]。在5种TMG中，端粒酶相关蛋白1 rs 1713449 SNP被确定为CH-B患者发生HCC和总生存率的最重要危险因素。此外，neurocan（NCAN）基因的遗传变异是ALD患者发生HCC的危险因素。NCAN是细胞外基质内的硫酸软骨素蛋白聚糖;它在神经元组织中表达，并参与脑发育和重塑[9]。此外，NCAN是NAFLD发展的风险因素，因为它也在肝脏中表达[10]。Nischalke等人[11]报道NCAN rs 2228603 T等位基因是ALD患者发生HCC的重要风险因素。根据全基因组关联研究，PNPLA 3基因（G等位基因rs738409）的变异是NAFLD发生和严重程度的最重要遗传风险因素[12，13]。PNPLA 3基因的G等位基因与日本人群中的Matteoni 4型非酒精性脂肪性肝炎（NASH）密切相关[14]。关于HCC与PNPLA 3基因之间的关系，PNPLA 3 G等位基因与晚期纤维化风险增加相关，并且是NASH或ALD相关肝硬化患者发生HCC的独立风险因素[15，16]。Ueyama等人[17]首先报道PNPLA 3的遗传变异与T2 DM患者的HCC发展相关。虽然T2 DM是HCC的重要危险因素，但相关的遗传背景仍不清楚。此外，据认为，
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-o 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