OGG or not OGG? That is the question.

Lung cancer has one of the worst survival rates of all cancers and this tends to be because at the time when symptoms appear it is so advanced there are few treatment options remaining.  The saddest fact about this is that the main cause of lung cancer is smoking – a voluntary social habit.  But have you ever wondered how some life-long heavy smokers never get lung cancer, yet someone who has never smoked (except passively maybe) does?  The explanation is being explored and something substantial has been discovered so it’s possibly not just down to luck, after all.

The reason why we see these “inconsistencies” may be down to the activity of a specific protein, called an enzyme, that we have in our bodies; but before I get to that part I need to start here:  Have you ever seen those advertisements boasting that certain food and drink products contain this-and-that anti-oxidant?  So, what of these so-called oxidants that we’re being told to be so “anti” about?  Well, when oxygen is metabolised in the body, reactive oxygen species (also known as “free radicals”) are produced.  Although free radicals are natural by-products, if they are not stabilised by anti-oxidants they can cause mutations in our DNA that may ultimately lead to cancer (carcinogenesis).  Free radicals can originate from a number of sources, particularly environmental factors such as radiation and UV light.  Smoking cigarettes also increases the amount of free radicals in the body, creating a link between smoking and the development of lung cancer.  There still remains some debate over whether or not the anti-oxidants from our diet such as beta-carotene or vitamins A, C and E are effective enough to actually prevent cancer, though they have been shown to provide some protection from the oxidative stress caused by the free radicals.

The origins of free radicals

So, again, why then do some smokers get lung cancer and others don’t?

One explanation may lie with the activity of the verbosely named enzyme “8-oxoguanine DNA glycosylase”, or OGG for short.  OGG acts to repair damaged DNA by removing the most common mutagenic base byproduct, 7,8-dihydro-8-oxoguanine, caused by the oxidative damage to guanine (one of the four bases that make up our DNA and RNA).  A significant relationship has been found between OGG activity and the prevalence of lung, head and neck and also colonic tumours.  Accordingly, individuals who developed lung cancer demonstrated lower OGG activity than controls who did not, which particularly highlights that the link between smoking and developing lung cancer was not just related to the fact that an individual smokes cigarettes, there’s more to it than that.  In fact, non-smokers with low OGG activity were actually of a similar risk to developing lung cancer as smokers with high OGG activity.  It comes as no surprise then that individuals at the greatest risk are smokers with low OGG activity.

Interestingly, when comparisons of OGG activity were made between “at diagnosis” of head and neck cancer and “at post-successful treatment”, it was found that the activity remained at an approximate constant level.  This suggests that in head and neck cancer, OGG activity is not an effect of the cancer.  Opposingly, however, OGG has been found to actually increase in colorectal cancers, which must suggest that OGG activity is not a constant in all cancers but sometimes upregulated, perhaps in a vain attempt to prevent tumour advancement.

Variations in the observable outcome of OGG activity (known as the phenotype) have been considered to be related to the individuals genetic information stored in our DNA (known as genotype).  A phenotype is determined by the combination of instructions set out by genes and their “partners” on sister chromosomes.

A karyotype showing the numbered pairs of chromosomes in a boy (XY)

Here’s a brief crash course in basic genetics before I explain this point any further: Inside the nucleus of every cell, our DNA is coiled up tightly into 46 structures known as chromosomes (except in sperm and egg cells, which only have 23).  Chromosomes occur in pairs (one half from your mother and one half from your father) and are numbered from 1 to 22 with the additional sex-determining chromosomes X and Y.  All of our genes are (normally) found at specific locations, or loci, on these chromosomes, for example, you and I will both have a gene at the same, specific spot on chromosome 2 that holds the instructions for making a type of collagen.  Similarly, as gender is determined by the combination of X and Y (XX for girl and XY for boy), our other phenotypic traits are determined by the combined information of genes at the same loci within a pair of chromosomes (please note: some phenotypes are determined by combinations of genes at different loci on the same or a different chromosome, but for simplicity I shall remain with this example).  These paired genes at specific loci are known as alleles, and sometimes information from one allele can dominate another so that only this gene presents as a phenotype; in other cases neither are dominant and so the phenotype presents as a mix of the information from both alleles and this is known as co-dominance.

Allele pairing for collagen on chromosome 2. (M=from mother, F=from father)

Back to OGG activity, the genetic instructions and variations in this enzyme’s activity is thought to be determined by the combination of the pair of alleles of the OGG gene (on chromosome 3) known as Ser326 and Cys326, of which their are three possibilities: Ser326/Ser326, Ser326/Cys326 or Cys326/Cys326.  Studies investigating cancer of the larynx and lung have found Ser326 to induce higher OGG activity when compared to the Cys326 variant. These studies also describe how the allele combinations of Ser/Cys and Cys/Cys are significantly linked to increased risk of developing cancer, particularly amongst heavy smokers and moderate to heavy alcohol drinkers, but do not change the risks for former to moderate smokers/alcohol drinkers.  With this in mind, therefore, it is believed that studying the OGG activity itself is more effective than genotyping because it measures the true effect in vivo.  The significance of the Ser/Cys genotypic combinations must not, however, be disparaged.

Could we benefit from an OGG test?

This test would mark the way forward to preventing, not treating cancer; a paradigm for future tests for other cancers that can predict predisposition on a bespoke, personal level.  Presently, there are no such tests in the health service that are used to assess your OGG activity.  Do you not think it would be comforting to know that you had a Ser/Ser combination of alleles?  Alternatively, imagine knowing you were definitely in the “high risk” group for developing lung cancer, would you be disinclined to smoke then (if not intuitively already, of course)?  Anti-smoking campaigns are not enough to reduce the incidence and mortality caused by smoking; we need to make it personal for the individual because everybody is different.

Your body may be trying to tell you something.  Wouldn’t you like to know?

Other useful and informative links:

When the proposal of the OGG test hit the news: here

For a detailed description of how OGG activity is measured: here

Report in Nursing Times.net about the OGG test: here.

Image Credit:

Free radicals image used with permission from Rebecca Fairchild at www.thefoodadvicecentre.co.uk