**13. References**

532 DNA Repair

involved in MMR is not known, recent studies suggest an influence of SNPs or biochemical interaction between components of the MMR pathways or on epigenetic mediated

Several common polymorphisms in DNA repair genes representing different repair pathways have been reported. Many studies have been carried out to elucidate the association between DNA repair gene polymorphisms and cancer susceptibility. But studies have shown inconsistent associations. The impact of many these polymorphisms on repair phenotype and cancer susceptibility remain uncertain (Berwick & Vineis, 2000; Au et al., 2004). In a study on 5 DNA repair genes (XRCC1 Arg194Trp and Arg399gln, PARP Val762Ala and Lys940Arg, XPD Asp312Asn and Lys751Gln, OGG1 Ser326Cys MGMT Leu84Phe) in Singaporean Chinese population, Stern et al., (2007) provided support to the hypothesis that selected variants in DNA repair genes may contribute to colorectal cancer risk and may modify the effects of relevant life style risk factors that have been inconsistently associated with the disease. This study which reported the overall effects of PARP on colorectal cancer risk and XRCC1 SNPs as modifiers of the effects of smoking and alcohol on colorectal cancer risk, also highlighted the role of the base excision repair pathway in colorectal carcinogenesis. Vinies et al (2009) conducted meta-analyses of 241 associations between variants in DNA repair genes and cancer and had found sparse association signals with strong epidemiological credibility. Using 1087 datasets and publicly available data from genome wide association platforms, meta-analysis using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. Thirty one nominally statistically significant (P<0.05 without adjustment for multiple comparisons) associations were recorded for 16 genes in dominant and/or recessive model analyses (BRCA2, CCND1, ERCC1, ERCC2, ERCC4, ERCC5, MGMT, NBN, PARP1, POL1, TP53, XPA, XRCC1, XRCC2, XRCC3 and XRCC4). XRCC1, XRCC2, TP53, and ERCC2 variants were each nominally associated with several types of cancer. Three associations were graded as having "strong" credibility, another four had "modest" credibility and 24 had "weak" credibility based on Vinies criteria. Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1-77 T>C (dominant-model) with lung cancer had P≤ 0.0001 and retained P≤ 0.001 even when the first published studies on the respective associations were excluded. The analyses suggested that the vast majority of postulated associations between DNA repair alleles and cancer risk have not been replicated sufficiently to give them strong credibility. This meta-analysis implies that larger scale studies would be necessary to establish specific associations of genetic variants in DNA repair and cancer and that the added risk conferred by single variants in DNA repair genes may be small. In another recent meta analysis, (Kiyohara et al.) found XPA G23A, OGG1 Ser326Cys and XPD Lys751Gln

functional regulation (Chen et al., 2007).

polymorphisms were associated with lung cancer risk .

In SNP association studies, the most important critical point is associated with often too small size of cohort of cases and controls, resulting in a low statistical power and false, by chance, positive or negative outcomes. Another important aspect concerns inclusion of different ethnic groups. Different results may be expected due to intrinsic difference in genetic background among Caucasians, Asians, Afro Americans and other ethnic groups.

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**27** 

 *Denmark* 

**Polymorphisms in Nucleotide Excision Repair** 

*Danish Cancer Society & National Research Centre for the Working Environment* 

Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens through direct binding of metabolites (adduct formation). If not repaired the DNA lesions may lead to genetic instability, mutagenesis and oncogenesis. Thus, DNA

Environmental factors are likely to cause damage to DNA through direct binding of metabolites (adduct formation). The nucleotide excision repair (NER) pathway is the

Common occurring single nucleotide polymorphisms (SNPs) in genes involved in DNA repair may possibly contribute to the variation in the capacity of repair of bulky DNA

The present book chapter includes a systematic review of the available scientific literature on associations between SNPs in genes involved in NER and risk of colorectal adenomas and colorectal cancer. The present review of colorectal cancer studies includes 19 studies on 22 different SNPs. The review is focused on SNPs in four genes: *XPD*, *XPC*, *XPA* and *ERCC1*  encoding the essential components of NER: xeroderma pigmentosum complementation group A, C, and D and excision repair cross complementary group 1 and risk of colorectal adenomas and colorectal cancer, and on interaction between the polymorphisms and

The NER polymorphisms studied in the work underlying this book chapter include the polymorphisms: *XPD* Lys751Gln*, XPD* Asp312Asn*, XPA* G23A, *XPC* Lys939Gln, and *ERCC1* 

Colorectal cancer is the third most common cancer and the leading cause of cancer deaths in Western industrialised countries. Thus, every year nearly one million people worldwide develop colorectal cancer. Lifetime risk of colorectal cancer may reach 6% of the population in the Western industrialised countries (Jemal et al., 2006). The age-specific incidence of colorectal cancer increases sharply after 35 years of age, with approximately 90% of cancers

adducts. Hence, these SNPs may be important biomarkers of susceptibility to cancer.

**1. Introduction** 

Asn118Asn.

**1.2 Colorectal cancer** 

repair constitutes a first line of defence against cancer.

various life style factors in relation to colorectal cancer risk.

**1.1 Single nucleotide polymorphisms** 

primary mechanism for removal of large and bulky adducts from DNA.

**Genes and Risk of Colorectal Cancer:** 

**A Systematic Review** 

Rikke Dalgaard Hansen and Ulla Vogel

