Abstract
BackgroundLocal 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.ResultsMolecular 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.ConclusionsWe 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.
Highlights
Local sequence context is known to have an impact on the mutational pattern seen in cancer
By switching the thymine natively found in the KRAS sequence for a cytosine and a methylated cytosine we were able to study the similarities between methylated cytosine and thymine, both of which have a methyl group attached to the fifth carbon
Using a combination of molecular dynamics (MD) simulations and Multivariate statistical analysis (MVA), we have investigated structural distortion caused by a bulky adduct at guanines within mutational hotspots and non-hotspot sequences in KRAS, NRAS and HRAS
Summary
Local sequence context is known to have an impact on the mutational pattern seen in cancer. The local DNA sequence context and methylation status of the sequence impacts upon the carcinogen binding frequency, the level of damage, the rate of repair and subsequent mutation pattern, or signature [8]. Alexandrov et al, have published an extensive collection of studies determining the mutational patterns in cancer including where they associated mutational signatures with tobacco smoking [8]. They determined a signature dominated by C > A (G > T) mutations, a signature they are able to replicate in vitro with benzo[a]pyrene (BaP) exposure (cosine similarity = 0.94). Others have proposed that G > T mutations are caused by derivatives of BaP [9,10,11] including metabolite trans( +)
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