In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors.
In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors.
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DOI：
10.1101/gr.230219.117
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发表时间：
2018-05
期刊：
影响因子：
7
通讯作者：
Rozen SG
中科院分区：
文献类型：
--
作者：
Boot A;Huang MN;Ng AWT;Ho SC;Lim JQ;Kawakami Y;Chayama K;Teh BT;Nakagawa H;Rozen SG
顺铂与DNA反应，从而可能产生一种特征性的体细胞突变模式，称为突变特征。尽管顺铂广泛用于癌症治疗及其在继发性恶性肿瘤中的作用，但其突变特征尚未被描述。我们假设顺铂的突变特征可以作为一个生物标志物，以确定顺铂诱变在可疑的继发性恶性肿瘤。了解哪些组织有发生顺铂诱导的继发性恶性肿瘤的风险，可以为顺铂化疗后继发性恶性肿瘤的无创监测提供指导。我们对10个顺铂暴露的MCF-10A和HepG 2细胞的独立克隆进行了全基因组测序，并根据侧翼序列、转录链偏倚和其他特征描绘了单核苷酸和二核苷酸突变的模式。我们使用mSigAct签名存在测试和非负矩阵因子分解来搜索肝细胞癌和食管腺癌中的顺铂突变。所有克隆显示出高度一致的单和二核苷酸取代模式。二核苷酸取代的比例很高：8.1%的单核苷酸取代是二核苷酸取代的一部分，这可能是由于顺铂倾向于在DNA中的嘌呤碱基之间形成链内和链间交联。我们确定了9例肝细胞癌和3例食管腺癌中可能的顺铂暴露。所有临床数据可用的肝细胞癌和所有食管癌确实有顺铂治疗史。我们实验描绘了顺铂的单和二核苷酸突变签名。该特征使我们能够以高置信度检测人肝细胞癌和食管腺癌中既往顺铂暴露。
Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatin's mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for noninvasive monitoring for secondary malignancies after cisplatin chemotherapy. We performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells and delineated the patterns of single and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and nonnegative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. All clones showed highly consistent patterns of single and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatin's propensity to form intra- and interstrand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in nine hepatocellular carcinomas and three esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. We experimentally delineated the single and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence.
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DOI：
10.1186/s41021-016-0037-9
发表时间：
2016
期刊：
Genes and environment : the official journal of the Japanese Environmental Mutagen Society
影响因子：
--
作者：
Hashimoto S;Anai H;Hanada K
通讯作者：
Hanada K
DOI：
10.1073/pnas.1614430113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Hu, Jinchuan;Lieb, Jason D.;Adar, Sheera
通讯作者：
Adar, Sheera
影响因子：
4.1
作者：
Harrington, Chris F.;Le Pla, Rachel C.;Farmer, Peter B.
通讯作者：
Farmer, Peter B.
影响因子：
3.3
作者：
Behmand, B.;Marignier, J. -L.;Sanche, L.
通讯作者：
Sanche, L.
影响因子：
4.5
作者：
Dugbartey GJ;Peppone LJ;de Graaf IA
通讯作者：
de Graaf IA