Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains.
Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains.
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DOI：
10.1002/ijc.24743
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发表时间：
2010-01-01
影响因子：
6.4
通讯作者：
Malkinson, Alvin M.
中科院分区：
文献类型：
--
作者：
Dwyer-Nield, Lori D.;McQuillan, Jay;Hill-Baskin, Annie;Radcliffe, Richard A.;You, Ming;Nadeau, Joseph H.;Malkinson, Alvin M.
癌症易感性由敏感性和抗性等位基因之间的相互作用产生。我们采用小鼠染色体置换株来研究在化学诱导的肺癌发生过程中耐药等位基因如何影响敏感等位基因。C57 BL/6 J-Chr #A/J品系是通过选择性繁殖敏感的A/J和抗性C57 BL/6 J（B6）小鼠构建的，每个品系在另外的B6基因组内含有一对A/J染色体。Pas 1，负责这种差异应变响应尿烷致癌作用的主要位点，驻留在Chr 6，但C57 BL/6 J-Chr 6A/J小鼠（以下简称CSS-6）开发几个肿瘤后，一个单一的尿烷注射，这表明上位相互作用与其他B6等位基因。然而，CSS 6小鼠在慢性氨基甲酸乙酯暴露后发生了数十种肺肿瘤，这表明这些上位相互作用可以通过重复致癌物给药来克服。与A/J小鼠不同，但与B6小鼠相似，CSS 6小鼠对3-甲基胆蒽（MCA）诱导的肺癌具有抗性。如果在氨基甲酸乙酯暴露后给予BHT，则肿瘤多样性增加，表明Chr 6基因调节对化学诱导肿瘤促进的敏感性。与A/J肿瘤（主要是密码子61 A→ T转换）不同，CSS-6小鼠中乌拉坦诱导的肿瘤中的Kras突变与B6肿瘤相似（密码子61 A→G转换）。不在Chr 6上的DNA修复基因可能决定Kras突变的性质。CSS-6小鼠是测试候选基因调节肺癌发生能力的宝贵资源。
Cancer susceptibility results from interactions between sensitivity and resistance alleles. We employed murine chromosome substitution strains to study how resistance alleles affected sensitive alleles during chemically-induced lung carcinogenesis. The C57BL/6J-Chr#A/J strains, constructed by selectively breeding sensitive A/J and resistant C57BL/6J (B6) mice, each contain one pair of A/J chromosomes within an otherwise B6 genome. Pas1, the major locus responsible for this differential strain response to urethane carcinogenesis, resides on Chr 6, but C57BL/6J-Chr6A/J mice (hereafter CSS-6) developed few tumors following a single urethane injection, which demonstrates epistatic interactions with other B6 alleles. CSS6 mice developed dozens of lung tumors after chronic urethane exposure, however, indicating that these epistatic interactions could be overcome by repeated carcinogen administration. Unlike A/J, but similar to B6 mice, CSS6 mice were resistant to lung carcinogenesis induced by 3-methylcholanthrene (MCA). Tumor multiplicity increased if BHT administration followed urethane exposure, showing that a Chr 6 gene(s) regulates sensitivity to chemically-induced tumor promotion. Unlike A/J tumors (predominantly codon 61 A→ T transversions), Kras mutations in tumors induced by urethane in CSS-6 mice were similar to B6 tumors (codon 61 A→G transitions). DNA repair genes not located on Chr 6 may determine the nature of Kras mutations. CSS-6 mice are a valuable resource for testing the ability of candidate genes to modulate lung carcinogenesis.
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