BMJ  2006;332:1150-1152 (13 May), doi:10.1136/bmj.332.7550.1150

Analysis and comment

Cancer genetics

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

¹ National Cancer Institute, Bethesda MD 20892-7354, USA, ² University of Helsinki, Helsinki, Finland

The human genome map has started a hunt to find common genes that are associated with cancer. But new research questions the likelihood of success.

Huge resources are being invested in the search for common inherited genetic variants that increase susceptibility to cancer. However, these studies are expensive because they require large sample sizes to rule out false positive results (table).^{1 2} The US cancer genetic markers of susceptibility project (http://cgems.cancer.gov), for example, will cost $14m (£7.9m; 11m). In addition, large replication studies may still be necessary to confirm generalisability to other populations. For these studies to eventually lead to a clinical therapeutic benefit, common genetic variants that increase susceptibility to cancer must exist and it must be feasible to rigorously evaluate the clinical benefit of targeting these common genetic variants. Both these requirements require formal consideration.

View this table: [in this window] [in a new window]   Sample sizes required to make false positive results unlikely when testing association between genetic variant and cancer*

 

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 (121K): [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.^14-16 However, the variation in risk could also be explained by non-genetic risk factors such as defects in cellular communication^{3 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.

Difficulty showing clinical benefit

Even if we are incorrect, and if large studies detect true associations between common genes and common cancers, showing clinical benefit will still be difficult. Ideally, identification of a gene related to cancer would provide important biological insights that suggest a modifiable risk factor or lead to a new treatment. The first step to prove clinical benefit would be additional observational studies to confirm the effect of the modifiable risk factor. The second step would be a randomised trial to determine if benefits outweigh harms in asymptomatic people. Volunteers would need to be tested for the genetic variant, and those who had the variant randomised to an intervention or placebo. Such trials are likely to be both expensive and long. Because cancer is rare in asymptomatic people, very large sample sizes are required, typically 10 000 to 30 000.¹⁸ Even larger numbers of people have to have genetic testing to identify those suitable for randomisation.

If a randomised trial has already been conducted of an intervention targeted at the likely modifiable risk factor, an alternative design can be used that reduces the amount of genetic testing. The idea is to "piggy back" on the existing trial by using a nested case-control design to select all participants with cancer and a random sample without cancer for genetic testing. Such a nested case-control study was proposed for the further analysis of data from the breast cancer prevention trial, which showed that tamoxifen reduced the risk of breast cancer but at the substantial cost of harmful side effects.¹⁹ The goal of the nested case-control study was to identify a subset of participants with a gene who might have a greater reduction in breast cancer risk than the average participant so that benefits would outweigh harms. In the design calculations two types of genes were considered: rare genes with high genetic relative risk and common genes with low relative risk. It was found that only rare genes with high relative risk would be likely to be detected with a benefit that outweighed harms. If this case is a guide, the approach would not be suitable for use with common genes.

Conclusion

The search for common cancer susceptibility genes faces important methodological and practical challenges for cancer prevention, given the small chance that such genetic variants exist and the difficulty and expense of proving substantial clinical benefit if they do exist. Enthusiasm for this new field of research should not precipitate unwarranted expectations.

Summary points Studies to detect common cancer susceptibility genes are expensive because they require large sample sizes Evidence from biology, migration studies, and twin studies suggests that common cancer susceptibility genes are unlikely Even if susceptibility genes were identified, further large studies would be needed to show clinical benefit

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An explanation of sample size calculations for gene-cancer association studies is on bmj.com

Contributors and sources: SGB and JK have analysed Nordic twin data and SGB has investigated nested case-control studies for studying genetic effects in randomised trials. JK works as a genetic epidemiologist for the Finnish National Public Health Institute. SGB wrote the initial draft and JK provided substantive comments and substantial editing. SGB is the guarantor.

Funding: JK is supported by the Genomeutwin project (European Union contract QLG2-CT-2002-01254).

Competing interests: None declared.

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(Accepted 9 March 2006)

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Response to the article „Common susceptibility genes for cancer: search for the end of the rainbow” BMJ 2006; 332; 1150-1152 by SG Baker, J Kaprio.

Jan Lubinski
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Response to letter from Professor Lubinski regarding "Common susceptibility genes for cancer: search for the end of the rainbow"

Stuart G. Baker, et al.
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Low penetrance cancer genes are worth searching for

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Failure of cancer genetics; Are we ready to accept the argument for transfer of resources to observational and experimental research in cancer biology ?

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Response to letter by Professor Luzzatto regarding “Common susceptibility genes for cancer: search for the end of the rainbow”

Stuart G. Baker, et al.
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