Tobacco and Public Health - TCSC Indonesia

DNA repair
As previously alluded to, variation between individuals in DNA repair capacity may be
a risk factor for cancer. There are several processes (and associated genes) involved in
DNA repair including detection of DNA damage (TP53), nucleotide excision repair
(XPD and XPF) and double-strand/recombination repair (XRCC1 and XRCC3). A
recent paper by Wu et al. (2002) extensively examined three polymorphisms in p53
and found each variant, along with variant haplotypes, to be associated with an
increased risk of lung cancer. Functional effects of variant alleles were tested in vitro,
and lymphoblastoid cell lines with all wild type alleles had significantly higher apoptotic
indices and DNA repair capacity, than those with at least one variant, suggesting
the effect of the polymorphisms may be to inhibit p53 function. Despite their low penetrance,
these variant alleles are quite prevalent in the population (albeit ethnicity
dependent), leading to a high population attributable risk.
Several polymorphisms in DNA repair enzymes have been examined, XRCC1 and
XPD being the most frequently studied. XRCC1 variant alleles have reduced base excision
repair capacity and are associated with increased population-dependent risks of
bladder cancer (Stern et al. 2001) and breast cancer (Duell et al. 2001), but conflicting
results for lung cancer (Park et al. 2002). A number of fairly prevalent (~30%) polymorphisms
in XPD have been described and until recently their influence on function
was unclear. The functional effect of variation within this gene has now been associated
with increased levels of aromatic adduct, and also with increased lung cancer risk.
Other targets
Other targets to consider include enzymes involved in tumour invasion and metastasis,
such as collagenases. Variation in the matrix metalloproteinase-1 gene (MMP-1) promoter
region partially regulates gene expression and appears to increase risk of lung
cancer; this risk was also further elevated in smokers (Zhu et al. 2001). The association
was also less evident in former smokers and more evident in heavy smokers.
Summary
MICHAEL MURPHY ET AL.
In conclusion conditional upon becoming a regular smoker, which may itself be genetically
influenced, there are several key areas which may impact on the genetic susceptibility
of an individual. The complex multistage process that leads a smoker to develop cancer
will no doubt involve multiple (low penetrant) gene effects both dictating exposure and
the host response. Gene–environment interactions are of particular interest, i.e. for a
given environmental exposure (smoking) does the risk of cancer differ with respect to
polymorphic variation? We have examined here only those genes thought to contribute
to risk, not the myriad of genes involved in cellular changes prior to progression to malignancy.
Using a candidate gene approach, the importance of haplotypes will also become
more evident particularly when relating variation with protein function or expression.
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