Genetic profiling of intrahepatic cholangiocarcinoma.
Genetic profiling of intrahepatic cholangiocarcinoma.
复制标题
肝内胆管癌的基因分析。
DOI：
10.1097/mog.0b013e3283523c7e
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发表时间：
2012-05
影响因子：
2.5
通讯作者：
Thorgeirsson SS
中科院分区：
文献类型：
--
作者：
Andersen JB;Thorgeirsson SS
肝内胆管癌（ICC）是一种预后不佳的难治性疾病。临床管理方面的有限成功和世界范围内发病率的持续增加使ICC成为最致命和增长最快的恶性肿瘤之一。然而，最近全基因组技术的进步结合了综合多维分析方法的应用，已经开始为ICC的潜在生物学特性提供详细的见解，并确定了新的治疗机会。与其他癌症相比，ICC的基因组研究一直很有限。我们和其他人最近获得了用于全基因组分析的大型ICC患者队列。在我们的研究中，ICC患者的样本来自三个癌症中心，并进行了综合遗传和基因组分析。我们提供了关于发病机制和最佳治疗方案的新见解，表明存在独特的患者亚类，部分基于KRAS突变和受体酪氨酸激酶信号传导水平的增加。预后最差的患者组的特点是调节炎症和蛋白酶体活性的基因转录富集，提示酪氨酸激酶抑制剂和抗炎药物联合治疗是这些患者的新治疗选择。我们严格审查了ICC全基因组研究的进展，包括遗传谱，转录组学和表观基因组学。与其他肝胆疾病相比，目前将这些技术应用于档案样本方面的限制以及获得新鲜冷冻材料的机会不足，是导致基于组学的ICC调查实施延迟的部分原因。因此，选定的候选单基因研究也将进行讨论。
Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. In comparison with other cancers genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single gene studies will also be discussed.