Local sequence context is known to have an impact on the mutational pattern seen in cancer. The RAS genes and a smoking carcinogen, Benzo[a]pyrene diol epoxide (BPDE), have been utilised to explore these context effects. BPDE is known to form an adduct at the guanines in a number of RAS gene sites, KRAS codons 12, 13 and 14, NRAS codon 12, and HRAS codons 12 and 14. Molecular modelling techniques, along with multivariate analysis, have been utilised to determine the sequence influenced differences between BPDE-adducted RAS gene sequences as well as the local distortion caused by the adducts. We conclude that G:C > T:A mutations at KRAS codon 12 in the tumours of lung cancer patients (who smoke), proposed to be predominantly caused by BPDE, are due to the effect of the interaction methyl group at the C5 position of the thymine base in the KRAS sequence with the BPDE carcinogen investigated causing increased distortion. We further suggest methylated cytosine would have a similar effect, showing the importance of methylation in cancer development.

中文翻译：

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致癌物诱导的 RAS 基因同工型 DNA 结构扭曲差异；局部序列的重要性

已知局部序列背景对癌症中的突变模式有影响。RAS 基因和吸烟致癌物苯并[a]芘二醇环氧化物 (BPDE) 已被用来探索这些背景影响。已知 BPDE 在许多 RAS 基因位点、KRAS 密码子 12、13 和 14、NRAS 密码子 12 以及 HRAS 密码子 12 和 14 的鸟嘌呤处形成加合物。分子建模技术以及多变量分析已被用于确定序列影响 BPDE 加合的 RAS 基因序列之间的差异以及加合物引起的局部变形。我们得出的结论是，肺癌患者（吸烟者）肿瘤中 KRAS 密码子 12 处的 G:C > T:A 突变主要由 BPDE 引起，是由于 BPDE 的 C5 位置上的相互作用甲基的影响所致。 KRAS 序列中的胸腺嘧啶碱基与 BPDE 致癌物一起被调查导致扭曲增加。我们进一步表明甲基化胞嘧啶也会产生类似的作用，显示甲基化在癌症发展中的重要性。