Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits.
Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits.
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DOI：
10.1016/j.jhep.2013.10.014
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发表时间：
2014-02
影响因子：
25.7
通讯作者：
Thorgeirsson, Snorri S.
中科院分区：
文献类型：
--
作者：
Marquardt, Jens U.;Seo, Daekwan;Andersen, Jesper B.;Gillen, Matthew C.;Kim, Myoung Soo;Conner, Elizabeth A.;Galle, Peter R.;Factor, Valentina M.;Park, Young Nyun;Thorgeirsson, Snorri S.
人类肝癌的发生是一个多步骤的过程，从发育异常病变开始到早期癌（eHCC），最终进展为HCC（pHCC）。然而，驱动癌前病变恶变的连续分子改变尚不清楚。这种信息的缺乏是临床管理风险患者的一个主要挑战。我们将下一代转录组测序应用于来自8名患有B型肝炎感染的HCC患者的无肿瘤周围肝脏（n=7）、低级别（n=4）和高级别（n=9）异型增生病变、eHCC（n=5）和pHCC（n=3）。对肝癌发生过程中的基因组改变进行了遗传和转录组学变化的综合分析。我们报告说，包括eHCC在内的早期病变的转录组的变化是温和的，令人惊讶的同质性。广泛的遗传改变和随后的预后不良信号通路的激活仅发生在肝癌发生的晚期，并集中在TGFβ、WNT、NOTCH和EMT相关基因上，突出了pHCC的分子多样性。我们进一步确定IGFALS作为一个关键的遗传决定因素，优先下调pHCC。我们的研究结果为HCC风险患者的分子分层和治疗选择定义了新的标志，并值得进行更大规模的前瞻性研究，以开发基于个性化下一代测序分析的改良临床决策算法。
Human hepatocarcinogenesis is as a multi-step process starting from dysplastic lesions to early carcinomas (eHCC) that ultimately progress to HCC (pHCC). However, the sequential molecular alterations driving malignant transformation of the pre-neoplastic lesions are not clearly defined. This lack of information represents a major challenge in the clinical management of patients at risk. We applied next-generation transcriptome sequencing to tumor-free surrounding liver (n=7), low- (n=4) and high-grade (n=9) dysplastic lesions, eHCC (n=5) and pHCC (n=3) from 8 HCC patients with hepatitis B infection. Integrative analyses of genetic and transcriptomic changes were performed to characterize the genomic alterations during hepatocarcinogenesis. We report that changes in transcriptomes of early lesions including eHCC were modest and surprisingly homogenous. Extensive genetic alterations and subsequent activation of prognostic adverse signaling pathways occurred only late during hepatocarcinogenesis and were centered on TGFβ, WNT, NOTCH and EMT-related genes highlighting the molecular diversity of pHCC. We further identify IGFALS as a key genetic determinant preferentially down-regulated in pHCC. Our results define new hallmarks in molecular stratification and therapy options for patients at risk for HCC, and merit larger prospective investigations to develop a modified clinical-decision making algorithm based on the individualized next-generation sequencing analyses.
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影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
64.5
作者：
Li Z;Tuteja G;Schug J;Kaestner KH
通讯作者：
Kaestner KH
影响因子：
11.2
作者：
Alonso, Soledad R.;Tracey, Lorraine;Rodriguez-Peralto, Jose L.
通讯作者：
Rodriguez-Peralto, Jose L.
影响因子：
13.5
作者：
Kojiro, Masamichi;Wanless, Ian R.;Toniakos, Dina
通讯作者：
Toniakos, Dina
影响因子：
13.5
作者：
Keng, Vincent W.;Sia, Daniela;Sarver, Aaron L.;Tschida, Barbara R.;Fan, Danhua;Alsinet, Clara;Sole, Manel;Lee, Wai L.;Kuka, Timothy P.;Moriarity, Branden S.;Villanueva, Augusto;Dupuy, Adam J.;Riordan, Jesse D.;Bell, Jason B.;Silverstein, Kevin A. T.;Llovet, Josep M.;Largaespada, David A.
通讯作者：
Largaespada, David A.