**6. Acknowledgement**

552 DNA Repair

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

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

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,

In general, the studies suggest that the *XPD* Lys751Gln and *XPD* Asp312Asn polymorphisms may be associated with risk of colorectal adenomas with the possibility of interaction with smoking and alcohol consumption. The reported studies of polymorphisms in *XPC* and *XPA* in relation to risk of colorectal cancer are few, but the results are relatively consistent: In general, no association of the polymorphisms in the genes involved in NER (*XPD*, *XPC*, *XPA* and *ERCC1*) was observed with risk of colorectal cancer. A possible interpretation of the results may be that the polymorphisms in the genes *XPD*, *XPC*, *XPA*  and *ERCC1* are not of major importance in colorectal cancer carcinogenesis, which points towards that lowered repair capacity of the NER pathway may not be a risk factor for

The results were generally inconsistent or too few to compare to highlight any trend and no strong associations were observed for risk of colorectal adenomas or colorectal cancer.

carcinogenesis.

proven to be a useful approach.

development of colorectal cancer.

**5. Conclusion** 

providing hypotheses for future functional studies.

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