Common susceptibility genes for cancer: search for the end of the rainbow

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Abstract
Common cancer susceptibility genes are unlikely Devoting a large research effort to searching for common cancer susceptibility genes has several problems. The first is that recent research suggests these genes are unlikely to exist or, if they do, are unlikely to have much of an effect on the incidence of cancer. The early phases of carcinogenesis seem to entail alterations in the stroma (supporting tissue) rather than a genetic mutation of the parenchyma (functional tissue).3 4 Thus genetic susceptibility to cancer of the parenchyma (except for rare genes related to familial cancer) would have a relatively small role in the early stages of carcinogenesis. Moreover, a recent study could not find conclusive evidence of genetic alterations in the stroma,5 further diminishing the probable role of genetic susceptibility in early stage carcinogenesis. View larger version: In this window In a new window DNA chip analysis comparing gene expression in normal and cancerous prostate cells Credit: VERONIQUE BLANC AND QIN WANG/WELLCOME PHOTO LIBRARY In addition, the rapid changes in cell morphology needed for evolving cancer cells to have a growth advantage over other cells are likely to require large genetic rearrangements6 rather than single polymorphic changes. Of course, genetic mutations could also affect concentrations of hormones or growth factors, which might affect the tumour microenvironment. But these concentrations would also be affected by environmental factors. A second reason to play down the role of common genetic susceptibility genes is migration studies suggesting that environmental, dietary, or lifestyle changes have a large effect on the incidence of cancer.7 8 These studies show changes in incidence within one or two generations, which is probably too quick to be related to the introduction of new cancer susceptibility genes. A final reason to be sceptical of the role of common genetic susceptibility mutations in the cause of cancer comes from results from a Nordic study of cancers in twins.9 By analysing data from monozygotic (identical) and dizygotic (fraternal) twins, the authors showed that genetic susceptibility made only a small to moderate contribution to the incidence of cancer.9 The results support the argument for the primacy of environmental effects. Risch questioned the study's conclusions, using a mendelian model to show that the data could be consistent with a gene for cancer susceptibility with a low genetic relative risk.10 However, the model was unrealistic because it assumed independence of cancer incidence among twins without a cancer susceptibility gene.11 This is unlikely given that twins tend to have shared experiences, exposures, habits, and cancer screening behaviour (as would family members in general). A more realistic mendelian model that allowed dependence of cancer incidence among twins without genetic susceptibility estimated that the fraction of cancers with a susceptibility genotype would be 0.09 to 0.22 for prostate cancer, 0.08 to 0.14 for breast cancer, and 0.05 to 0.13 for colorectal cancer.11 Even these estimates are probably high because environmental factors were not modelled in the twin study and environmental factors among twins are likely to be similar. Moreover, the model fit to the twin data estimated a low prevalence for a cancer susceptibility genotype and a high genetic relative risk, as would be found in rare genes typically identified by mendelian inheritance patterns in pedigrees.12 13 By contrast, most research is focused on identifying common single nucleotide polymorphisms with a low genetic relative risk. Studies purporting to show a high likelihood of association between common low penetrance genes and cancer rely on less plausible assumptions than the Nordic twin study. For example, variations in the risk of secondary cancers have been argued to be best explained by variations in genetic risk.14 15 16 However, the variation in risk could also be explained by non-genetic risk factors such as defects in cellular communication3 4 or epigenetic mechanisms such as methylation of DNA. A meta-analysis of replicate studies after an initial positive finding found an association between a common gene and head and neck cancer.17 Although the authors discounted chance or bias in publishing studies that had significant results, substantial residual publication bias could have remained because of preferential submission and publication of studies that do not contradict the original reports even if the negative results were significant. Importantly, the same study found no association between a common genetic variant and breast cancer.