G->T Trans Versions
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Before we dive into the specifics, let's take a look at what Trans Versions are
When mutagens such as ultraviolet rays, which cause ionizing radiation or Tobacco, which cause alkylation project on DNA, they can cause alterations to the DNA strand. Essentially,we observe a point mutation in DNA in which a single (two ring) purine (A or G) is changed for a (one ring) pyrimidine (T or C), or vice versa.
If you would like a visual aid, check this video out
For our discussion of p53 and Lung Cancer, we will be focusing mainly on one specific type of Transversion, the G->T Transversion. An example is shown here for better visualization.
Some Facts:
It is also interesting to note that one of the most profilic G to T transversion hotspots in lung cancer is between codon 156 (CGC) and 157 (GTC). The codons 156 and 157 form a singular CpG between them which is has a high affinity to BPDE and is a binding target of BPDE.
A Controversial Paper on p53
Next, let's take a look at a controversial paper, namely "Human lung cancer and p53 The interplay between mutagenesis and selection" by Rodin and Rodin where they conducted a Monte-Carlo simulation. Their results showed:
(a) Complementary Base Substitutions in p53 from Lung Cancer Distinguish Smokers from Nonsmokers.
(b) The proportion of G to T transversions is significantly higher in smokers when compared to non-smokers.
In a somewhat questionable statement, Rodin and Rodin proposed that G to T transversions are not smoking induced, but rather dictated by selection as G to T transversions in p53 is not tissue specific. They claimed that there are
"no significant differences between smokers and non-smokers, either in the frequency of different types of mutations or in the frequency of their occurrence along the p53 gene". They also concluded that this selection is triggered by psychological stress. Their proposal was largely controversial as their data suggested that there was a pattern of correlation between smokers and loss of p53 functionality through G to T transversions. Additionally, it is seems that the data was manipulated as results were cherry picked to reach a conclusion.
Not surprisingly, quickly after the release of Rodin et al's paper, Hainut et al were alarmed by the conclusion reached by Rodin et al. In an effort to find the truth, Hainut et al reanalyzed all the primary literature available at the time on the mutation of p53 among smokers and nonsmokers additionally also analyzing other forms of cancers. Their data on p53 mutations on smokers and nonsmokers is shown below.
Here, their observation also found that the proportion of G to T transversions is significantly higher in smokers when compared to non-smokers as Rodin and Rodin did. In another observation they found that there were a number of mutational hotspots common to all cancers. They were able to produce a correlation between G to T transversion hotspots in lung cancers and sites of preferential formation of polycyclic aromatic hydrocarbon (PAH) (Such as BPDE) adducts along the p53 gene. This is especially interesting to note as PAHs are carcinogens in tobacco smoke that can replicate this mutation.
Animesh Dali | DePauw University
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