Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes.
Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes.
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DOI：
10.1093/carcin/bgw066
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发表时间：
2016-08
期刊：
影响因子：
4.7
通讯作者：
Tsuchihara K
中科院分区：
文献类型：
--
作者：
Mimaki S;Totsuka Y;Suzuki Y;Nakai C;Goto M;Kojima M;Arakawa H;Takemura S;Tanaka S;Marubashi S;Kinoshita M;Matsuda T;Shibata T;Nakagama H;Ochiai A;Kubo S;Nakamori S;Esumi H;Tsuchihara K
这些职业性胆管癌病例具有高突变负荷、链偏倚和独特的三核苷酸突变特征，表明患者可能暴露于常见的强诱变剂。诱变的潜在机制应进一步研究。胆管癌是一种相对罕见的癌症，但其发病率在全球范围内不断增加。虽然已经提出了几个危险因素，但大多数胆管癌的病因和发病机制仍不清楚。最近，日本大坂一家印刷公司的工人中报告了早发性胆管癌的高发病率。这些工人高度暴露于有机溶剂，主要是卤代烷，如1，2-二氯丙烷（1，2-DCP）和/或二氯甲烷。我们对4例印刷工人胆管癌进行了全外显子组分析。在印刷工人的胆管癌组织的基因组中，平均每Mb检测到44.8个体细胞突变，比在对照普通胆管癌组织中发现的高约30倍。此外，C：G-到-T：A的转换与大量的链偏差，以及独特的三核苷酸突变的变化GpCpY GpTpY和NpCpY NpTpY或NpApY是占主导地位的所有印刷工人的胆管癌基因组。这些结果与流行病学观察结果一致，即他们接触了高浓度的化学化合物。对接触1，2-DCP的鼠伤寒沙门氏菌菌株TA 100的全基因组分析显示，在印刷工人的胆管癌中部分重现了突变特征。虽然我们的研究结果提供了职业性胆管癌特有的突变特征，但该疾病的潜在机制应通过使用适当的模型系统并与其他癌症的基因组数据进行比较来进一步研究。
These occupational cholangiocarcinoma cases shared a high mutation burden, strand bias and unique trinucleotide mutational signatures, suggesting that the patients might have been exposed to a common strong mutagen. The underlying mechanisms of mutagenesis should be further investigated. Cholangiocarcinoma is a relatively rare cancer, but its incidence is increasing worldwide. Although several risk factors have been suggested, the etiology and pathogenesis of the majority of cholangiocarcinomas remain unclear. Recently, a high incidence of early-onset cholangiocarcinoma was reported among the workers of a printing company in Osaka, Japan. These workers underwent high exposure to organic solvents, mainly haloalkanes such as 1,2-dichloropropane (1,2-DCP) and/or dichloromethane. We performed whole-exome analysis on four cases of cholangiocarcinoma among the printing workers. An average of 44.8 somatic mutations was detected per Mb in the genome of the printing workers’ cholangiocarcinoma tissues, approximately 30-fold higher than that found in control common cholangiocarcinoma tissues. Furthermore, C:G-to-T:A transitions with substantial strand bias as well as unique trinucleotide mutational changes of GpCpY to GpTpY and NpCpY to NpTpY or NpApY were predominant in all of the printing workers’ cholangiocarcinoma genomes. These results were consistent with the epidemiological observation that they had been exposed to high concentrations of chemical compounds. Whole-genome analysis of Salmonella typhimurium strain TA100 exposed to 1,2-DCP revealed a partial recapitulation of the mutational signature in the printing workers’ cholangiocarcinoma. Although our results provide mutational signatures unique to occupational cholangiocarcinoma, the underlying mechanisms of the disease should be further investigated by using appropriate model systems and by comparison with genomic data from other cancers.