**4. Discussion**

In summary, this review, limited by the bias against publication of null findings, highlights the complexities inherent in epidemiological research and, particularly, in molecular epidemiological research on colorectal cancer. Studies on possible associations between SNPs in genes involved in defence of oxidative DNA damages and in nucleotide excision repair and risk of colorectal cancer have not obtained consistent results, why the issue of whether the SNPs are possible biomarkers of susceptibility for colorectal cancer is not satisfactorily clarified at present.

Polymorphisms in Nucleotide Excision Repair

Cancer Society (Grant number R2-A84-09-S2).

**6. Acknowledgement** 

**7. References** 

1037)

Genes and Risk of Colorectal Cancer: A Systematic Review 553

Overall, the role of genetic variants as SNPs in genes involved in NER is not satisfactorily clarified at present. It is possible that some of the SNPs may contribute to development of adenomas or colorectal cancer only in concomitance with certain dietary and life style factors. Furthermore, it may be only the joint effect of multiple polymorphisms that will provide us with information about genetic susceptibility for colorectal cancer. Larger carefully designed studies with stratified/adjusted analyses of gene-gene and geneenvironment interactions may be required in the future to achieve convincing statistically

Our special thanks go to Anne Tjønneland and Kim Overvad for giving us the opportunity to study the polymorphisms in the Danish prospective cohort Diet, Cancer and Health. We thank Anne-Karin Jensen and Lourdes M. Pedersen for excellent technical assistance for the genotyping in our studies on the Danish cohort. And a thank goes to our co-authors of the manuscripts on the Danish studies for the valuable feedback when writing the manuscripts. The work of the present book chapter was supported by a research grant from the Danish

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Sample size coupled with allele frequency may have influenced the validity of the results. Differences in the study design, like distribution of gender, age, topology, ethnicity and criteria for recruitment of comparison individuals may have contributed to the dissimilar findings. The application of large, well-designed association studies of the polymorphisms will make it statistically reasonable to make stratified analyses for obtaining information on risk factors in sub-groups and will generally decrease the risk of chance findings. Furthermore, studies including both cases with pre-stages of colorectal cancer and cancer cases will contribute with valuable information of the processes during colorectal carcinogenesis.

Most of the studies analyze individual polymorphisms in genes with modest effect in relation to risk of cancer. Cancer is a complex multigenic and multistage disease involving the interplay of many genetic and environmental factors. Hence, it is unlikely that a single genetic polymorphism in low-penetrance genes would have a dramatic effect on cancer risk. More information may be obtained from haplotyping multiple polymorphisms within genes or from combining multiple polymorphisms within pathways. The continued advances in SNP maps and in high-throughput genotyping methods will facilitate these analyses. Defining haplotypes and whole genome association studies may yield information on unexplored regions of the genome that has impact on colorectal cancer risk and development.

Colorectal cancer is probably caused by a complex interaction between many genetic and environmental factors over time. More and large studies with information on life style factors are required to assess these very possible gene-environment interactions. Identification of gene-environment interactions in cohorts with large relevant exposures has proven to be a useful approach.

Most environmental carcinogens require metabolic activation before they are able to form DNA damages. These activated forms may be detoxified or induce DNA repair or apoptosis. Thus, genetically determined susceptibility to colorectal cancer may depend on the balance among enzymes involved in metabolism and detoxification of carcinogens and on the balance between induction of DNA repair or apoptosis. Further investigations of the combined effects of polymorphisms between genes involved in these four mechanisms may help to clarify the influence of genetic variation in the carcinogenic process and may shed light on the complexities of the many pathways involved in colorectal cancer development, providing hypotheses for future functional studies.
