Mutational landscape of a chemically-induced mouse model of liver cancer.
Mutational landscape of a chemically-induced mouse model of liver cancer.
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DOI：
10.1016/j.jhep.2018.06.009
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发表时间：
2018-10
影响因子：
25.7
通讯作者：
Odom DT
中科院分区：
文献类型：
--
作者：
Connor F;Rayner TF;Aitken SJ;Feig C;Lukk M;Santoyo-Lopez J;Odom DT
致癌物诱导的小鼠肿瘤中随机点突变的高负荷。二乙基亚硝胺暴露后产生的肿瘤中的明显突变印记。Ras/MAPK通路基因突变驱动DEN引发的肝肿瘤发生。APC突变与DEN引发的肿瘤进展为癌相关。致癌物诱导的肝癌小鼠模型被广泛用于研究疾病的发病机制，并且对于验证候选疗法至关重要。这些模型可以概括人类疾病的分子和组织学特征。然而，目前尚不清楚驱动这些小鼠肿瘤基因组的基因组改变是否与人类肿瘤中发现的基因组改变相当。在此，我们提供了常用的肝细胞癌（HCC）小鼠模型的肿瘤的详细基因组特征。我们分析了暴露于二乙基亚硝胺（DEN）的小鼠肝脏肿瘤的全外显子组序列。比较了DEN治疗和未治疗小鼠的肝肿瘤与人HCC之间的突变特征。DEN引发的肿瘤具有高的、统一数量的体细胞单核苷酸变体（SNV），几乎没有插入、缺失或拷贝数改变，这与DEN的已知遗传毒性作用一致。暴露于DEN的肝细胞在产生的肿瘤外显子组中留下了可重复的突变印记，我们可以使用六个已知的COSMIC突变特征进行计算重建。这些肿瘤在许多癌基因和肿瘤抑制基因中携带了高度多样的低发病率、非同义点突变，反映了致癌物将SNV随机引入肝细胞基因组。我们确定了四个反复突变的基因，这些基因是该模型中HCC的假定致癌驱动因子。所有肿瘤均存在Hras基因第61位密码子、Braf基因第584位密码子和Egfr基因第254位密码子的激活热点突变。21%的肿瘤发生Apc截短突变，这些肿瘤仅为支持Wnt/β-连环蛋白信号转导失调在癌症进展中的作用的癌症。我们的研究提供了对肝癌常用致癌物模型中产生的肿瘤突变景观的详细了解，有助于将来使用该模型更好地了解人类疾病。小鼠模型被广泛用于研究癌症的生物学和测试潜在的治疗方法。在此，我们描述了致癌物诱导的肝癌小鼠模型中出现的肿瘤突变情况。由于癌症是一种由基因组改变引起的疾病，因此有关该小鼠模型中肿瘤突变模式和类型的信息应有助于其用于研究人类肝癌。
High burden of stochastic point mutations in carcinogen-induced murine tumours. Distinct mutational imprint in tumours arising after diethylnitrosamine exposure. Mutations in Ras/MAPK pathway genes drive DEN-initiated liver tumorigenesis. Apc mutations associated with progression of DEN-initiated tumours to carcinoma. Carcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and are critical for validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the genomic alterations driving these mouse tumour genomes are comparable to those found in human tumours. Herein, we provide a detailed genomic characterisation of tumours from a commonly used mouse model of hepatocellular carcinoma (HCC). We analysed whole exome sequences of liver tumours arising in mice exposed to diethylnitrosamine (DEN). Mutational signatures were compared between liver tumours from DEN-treated and untreated mice, and human HCCs. DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras, in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/β-catenin signalling in cancer progression. Our study provides detailed insight into the mutational landscape of tumours arising in a commonly used carcinogen model of HCC, facilitating the future use of this model to better understand the human disease. Mouse models are widely used to study the biology of cancer and to test potential therapies. Herein, we have described the mutational landscape of tumours arising in a carcinogen-induced mouse model of liver cancer. Since cancer is a disease caused by genomic alterations, information about the patterns and types of mutations in the tumours in this mouse model should facilitate its use to study human liver cancer.
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影响因子：
81.5
作者：
Llovet, Josep M.;Zucman-Rossi, Jessica;Gores, Gregory
通讯作者：
Gores, Gregory
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
13.5
作者：
Nam, SW;Park, JY;Lee, JY
通讯作者：
Lee, JY
影响因子：
10.7
作者：
SAITOU, N;NEI, M
通讯作者：
NEI, M
影响因子：
5.8
作者：
Saunders, Christopher T.;Wong, Wendy S. W.;Cheetham, R. Keira
通讯作者：
Cheetham, R. Keira