Genomics of Hepatocellular Carcinoma

Despite the growing incidence of hepatocellular carcinoma (HCC) due to increased hepatitis C virus infection and non-alcoholic steatohepatitis in Western populations, the genetic determinants of this cancer have yet to be established. A minority (15-20%) of HCC occurs in livers without cirrhosis or other chronic disease. Because the liver is functionally preserved in these patients and surgical resection of the tumor may be performed safely, and because of the scarcity of livers available for transplantation, non-cirrhotic patients undergo surgical resection for HCC treatment. These resected tumors present investigatory opportunities in two ways: First, they provide tumor specimen which have not been treated with chemotherapy and embolization. Second, the absence of cirrhosis may provide an unconfounded background from which to investigate the genetic tumorigenesis of HCC. In livers with cirrhosis, genetic instability is prevalent as assessed by assays for microsatellite instability, loss of heterozygosity and aberrant DNA methylation. In contrast, in livers without cirrhosis, the non-tumor tissue surrounding HCC have been found to have fewer genetic aberrations. It has been postulated that the pathologic process of cirrhosis may result in the accumulation of many "passenger"; as well as "driver" mutations, and that the examination of the HCC cancer genome may be facilitated in non-cirrhotic livers because of the absence of an accumulated background noise of mutations.]]>尽管西方人群中因丙型肝炎病毒（hepatitis C virus）感染与非酒精性脂肪性肝炎（non-alcoholic steatohepatitis）发病率上升，肝细胞癌（hepatocellular carcinoma, HCC）的患病率持续增长，但该癌症的遗传决定因素尚未明确。仅少数（15%~20%）的肝细胞癌发生于无肝硬化或其他慢性肝病的肝脏中。由于此类患者的肝脏功能仍得以保留，可安全实施肿瘤手术切除，且供肝移植资源匮乏，因此无肝硬化的肝细胞癌患者通常通过手术切除来治疗该病。这些切除获取的肿瘤组织具备两方面的研究价值：其一，它们提供了未接受过化疗与栓塞治疗的肿瘤标本；其二，无肝硬化的背景可作为未受混杂因素干扰的研究载体，用于探究肝细胞癌发生的遗传机制。在伴肝硬化的肝脏中，通过微卫星不稳定性（microsatellite instability）、杂合性缺失（loss of heterozygosity）与异常DNA甲基化（DNA methylation）检测可发现普遍存在的遗传不稳定现象。与之相反，在无肝硬化的肝脏中，肝细胞癌周围的非肿瘤组织所携带的遗传畸变更少。有假说提出，肝硬化的病理进程可导致大量“乘客”突变（passenger mutations）与“驱动”突变（driver mutations）的累积，而在无肝硬化的肝脏中研究肝细胞癌的基因组，可规避突变累积带来的背景噪声干扰，从而更便于开展相关分析。