All our lives we are continually bombarded by carcinogens--eg, sunlight, cigarette smoke, the products of internal oxidative metabolism--yet we don't all get cancer. Fewer than 20% of cigarette smokers develop lung cancer, for example.
One possibility is that individuals vary in terms of how well they repair the damage caused to DNA by carcinogens. If this is so, say scientists, and if differences in DNA-repair capacity correlate with the propensity to develop cancer, then research into DNA repair could help identify susceptible subgroups of people and so help reduce cancer risks.
"DNA repair is one of the front-line defences against cancer", says Rick Wood (Imperial Cancer Research Fund, London, UK). "The need to maintain genomic integrity presents a huge challenge to an organism", adds James Cleaver, professor of dermatology at the University of California (San Francisco, CA, USA). "A diploid human cell has 1·3 × 1010 bases, each of which has to be faithfully maintained and accurately copied during cell division." Defective repair can lead to cell death or mutation--and, by inference, carcinogenesis.
Cleaver's own work forms the basis for much of DNA-repair research. In 1989, Cleaver reported that xeroderma pigmentosum (XP), a rare inherited cancer syndrome, is caused by a defective nucleotide-excision repair pathway. This versatile pathway, which deals primarily with DNA damage caused by ultraviolet light, normally repairs any lesion that distorts the DNA double helix (figure). Up to 30 different gene products are involved in nucleotide-excision repair. Mutation of any one of seven of these genes can cause XP--six are shown on the figure, the seventh, XPE, is not part of the core repair system.
XP is an extreme example of the interaction between cancer-susceptibility genes and environmental triggers. When people homozygous for XP mutations are protected from sunlight and smoke, their cancer risk is the same as that of the general population, despite lacking both copies of an essential DNA-repair gene. Extrapolating from this, says Wood, we can learn something about how to view the effects of environmental carcinogens on populations.
XP gives us further clues to the interaction of genes and the environment. The classic hallmark of XP is hypersensitivity to sunlight and other mutagens, but some patients with mild XP do not develop cancer despite having a severe DNA-repair deficiency. Neuronal loss and developmental abnormalities can also occur in people with XP, depending on which XP gene is defective. This wide spectrum of disease phenotype suggests that variants of nucleotide-excision repair genes, and, by implication, variants of genes in other DNA-repair pathways, could be linked to the variation in cancer susceptibility seen in the general population.
This is what researcher Harvey Mohrenweiser, at the Lawrence Livermore National Laboratory (Livermore, CA, USA), is trying to find out. He is screening genes involved in different DNA-repair pathways in healthy individuals. "Potentially interesting aminoacid-substitution variants are quite common. We haven't yet defined their role as cancer susceptibility genes, but that will come from studies of possible associations of these variants with reduced repair capacity and mutagen sensitivity phenotypes, and from cancer epidemiology studies."
"The concept of genetic susceptibility to carcinogenic exposures must be factored into risk assessment", adds epidemiologist Margaret Spitz (MD Anderson Cancer Center, Houston, TX, USA). Spitz, who is studying mutagen-induced chromosomal sensitivity in lymphocytes from patients with tobacco-related squamous-cell malignancies, believes that altered DNA repair could underlie the mutagen sensitivity associated with cancer proneness. Patients with lung cancer, she says, seem to have a poorer repair profile than healthy people. Sensitivity to mutagens is not affected by dietary antioxidant intake or by smoking status, she adds.
Scientists at the US National Institute of Environmental Health Sciences (Bethesda, MD, USA) are also interested in what makes some people extra sensitive to environmental carcinogens. They are evaluating associations between cancer susceptibility and variations in genes that protect against environmental insults. 1000 people are to be screened for variants in about 200 candidate genes. These will be mostly polymorphic genes whose products inactivate or metabolise exogenous toxins such as cigarette tar and benzene--eg, cytochrome P450s, glutathione S-transferases, and N-acetyltransferases. But because of the link between mismatch-repair deficiencies and cancer, as in hereditary non-polyposis colon cancer, mismatch and base-excision repair-gene variants have also been included in the screen, says project head, Samuel Wilson.
The use of tiny DNA "chips", each containing thousands of oligonucleotide probes, will aid rapid screening. "Initially we will just be setting up a polymorphism database", says Wilson. "Later we will set up studies to link diseases with these DNA variants and combinations of variants. From other studies we already know, for instance, that the combination of exposure to aflatoxin, the presence of metabolism-gene polymorphism, and hepatitis-B infection raise cancer risk about 60-fold."
Wood, who together with colleagues in the Netherlands and USA isolated XPF last year, believes that understanding DNA repair could lead to improved cancer chemotherapy. "If XPF, or other repair genes, could be targeted specifically and turned off in tumour cells", he says, "anti-cancer drugs such as cisplatin, which work by damaging DNA, could be made more effective".
Dorothy Bonn