**1. Introduction**

538 DNA Repair

Tseng, R. C., Hsieh, F. J., Shih, C. M., Hsu, H. S., Chen, C. Y. & Wang, Y. C. (2009) Lung

Weston, A., Perrin, L. S., Forrester, K., Hoover, R. N., Trump, B. F., Harris, C. C. & Caporaso,

Whibley, C., Pharoah, P. D. & Hollstein, M. (2009) p53 polymorphisms: cancer implications.

Wood, R. D., Mitchell, M. & Lindahl, T. (2005) Human DNA repair genes. *Mutat Res,* 577**,**

Yin, J., Vogel, U., Ma, Y., Guo, L., Wang, H. & Qi, R. (2006) Polymorphism of the DNA

Zhou, G., Zhang, X., Lui, S., Lin, D., Liang, C. & Yang, X. (2001) [Pilot study on mutations of p53 gene in laryngeal carcinoma]. *Hua Xi Yi Ke Da Xue Xue Bao,* 32**,** 359-60, 434. Zhou, W., Liu, G., Miller, D. P., Thurston, S. W., Xu, L. L., Wain, J. C., Lynch, T. J., Su, L. &

Zienolddiny, S., Campa, D., Lind, H., Ryberg, D., Skaug, V., Stangeland, L., Phillips, D. H.,

*Cancer,* 115**,** 2939-48.

*Nat Rev Cancer,* 9**,** 95-107.

275-83.

*Epidemiol Biomarkers Prev,* 1**,** 481-3.

population. *Cancer Genet Cytogenet,* 169**,** 27-32.

non-small cell lung cancer. *Carcinogenesis,* 27**,** 560-7.

cancer susceptibility and prognosis associated with polymorphisms in the nonhomologous end-joining pathway genes: a multiple genotype-phenotype study.

N. E. (1992) Allelic frequency of a p53 polymorphism in human lung cancer. *Cancer* 

repair gene ERCC2 Lys751Gln and risk of lung cancer in a northeastern Chinese

Christiani, D. C. (2003) Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. *Cancer Epidemiol Biomarkers Prev,* 12**,** 359-65.

Canzian, F. & Haugen, A. (2006) Polymorphisms of DNA repair genes and risk of

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 repair constitutes a first line of defence against cancer.

Environmental factors are likely to cause damage to DNA through direct binding of metabolites (adduct formation). The nucleotide excision repair (NER) pathway is the primary mechanism for removal of large and bulky adducts from DNA.

#### **1.1 Single nucleotide polymorphisms**

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

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 various life style factors in relation to colorectal cancer risk.

The NER polymorphisms studied in the work underlying this book chapter include the polymorphisms: *XPD* Lys751Gln*, XPD* Asp312Asn*, XPA* G23A, *XPC* Lys939Gln, and *ERCC1*  Asn118Asn.

#### **1.2 Colorectal cancer**

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

Polymorphisms in Nucleotide Excision Repair

**2.2 Life style factors and DNA adduct formation** 

Genes and Risk of Colorectal Cancer: A Systematic Review 541

Air pollution is not an established risk factor for colorectal cancer in humans, although several studies have shown higher risk among workers exposed to diesel exhaust (Goldberg et al., 2001). Some studies have found an association between ambient air pollution and DNA adduct levels (Poirier et al., 1998; Hemminki et al., 1990b; Binkova et al., 1995; Palli et al., 2001; Nielsen et al., 1996a; Nielsen et al., 1996c), whereas others failed to find such an association (Kyrtopoulos et al., 2001; Peluso et al., 1998). DNA adduct levels are increased following occupational exposure among foundry and coke oven workers and among workers exposed to diesel exhaust (Hemminki et al., 1997; Hemminki et al., 1990a; Hemminki et al., 1994; Perera et al., 1988; Perera et al., 1994; Lewtas et al., 1997; Nielsen et al., 1996a; Nielsen et al., 1996b), while among fire-fighters (Rothman et al., 1993), traffic exposed policemen (Peluso et al., 1998) and aluminium workers (Yang et al., 1998), no

associations between occupational exposures and DNA adducts have been found.

tissue from smokers (Benhamou et al., 2003; Melikian et al., 1999).

*Air pollution* ↑ PAH

*Vegetables* ↓ -

*Fruit* ↓ -

association with risk of colorectal cancer.

drinking control group (Fang & Vaca, 1997).

*Tobacco smoking* ↑ PAH, NOC

*Alcohol* ↑ Acetaldehyde

*Red meat* ↑ PAH, NOC, HCA

*Processed meat* ↑ PAH, NOC, HCA

Table 1. Possible environmental risk and beneficial factors of colorectal cancer and their association with DNA adduct formation. Arrows indicate adverse (↑) or preventive (↓)

A growing body of evidence supports that avoidance of alcohol is recommended to prevent colorectal cancer (Correa Lima & Gomes-da-Silva, 2005). Acetaldehyde is the primary oxidative metabolite of ethanol. Acetaldehyde and malondialdehyde, the end-product of lipid peroxidation by reactive oxygen species, can combine to form the malondialdehydeacetaldehyde adduct, which is very reactive and avidly binds to DNA (Brooks & Theruvathu, 2005). The level of acetaldehyde DNA adducts in white blood cell DNA in alcohol abusers have been measured up to 13-fold higher than in subjects from the non-

Tobacco smoking is an established risk factor for development of adenomas (Ji et al., 2006), and recently an association between tobacco smoking and risk of colorectal cancer has been recognized by IARC. Following tobacco smoking, adducts formed by metabolites of NOCs and PAHs are not only located in airway tissue, but are also found in bladder and cervical

*Life style factor Risk of CRC DNA adduct formation* 

occurring in persons older than 50 years (Schottenfeld & Winawer, 1996) . The mean age at time for diagnosis in Danish colorectal cancer patients is approximately 70 years for men and 72 years for women (Iversen et al., 2005) . The disease develops either sporadically, as a part of a hereditary cancer syndrome, or induced by inflammatory bowel disease. Ten to fifteen percent of colorectal cancer cases are caused by hereditary syndromes (Schottenfeld & Winawer, 1996) .

Migrant studies and large international variation in incidence rates indicate that life style factors, including dietary, are associated with risk of colorectal cancer, but traditional epidemiological studies based on life style questionnaires and outcome have mostly failed in identifying the exact risk and beneficial factors. Our current knowledge of colorectal carcinogenesis indicates a multi-factorial and multi-step process that involves various genetic alterations and several biological pathways. An understanding of differences in individual susceptibility and better exposure assessment may be crucial in identifying life style risk factors and possible interactions between susceptibility and exposures in relation to risk of colorectal cancer.

#### **2. DNA adducts**

Several life style factors and dietary components are suggested to be associated with risk of colorectal cancer, listed in Table 1. The associations may possibly be caused by increased formation of DNA adducts.

#### **2.1 NOC, HCA and PAH**

N-nitroso compounds (NOCs) are present in tobacco smoke and in nitrate- or nitrite-treated meats (Hotchkiss, 1989; Hecht & Hoffmann, 1988). NOCs are alkylating agents able to react with DNA and form adducts. More than 85% of 300 NOCs tested for carcinogenicity in experimental animals were observed to be carcinogenic (Mirvish, 1995), but epidemiologic studies have been inconclusive in finding association between the exposure of NOCs and risk of various cancer forms in humans (Burch et al., 1987; Preston-Martin & Mack, 1991; Carozza et al., 1995), although an increased endogenous production of NOCs, suggested primarily by bacterial catalysis, are proposed associated to the etiology of colorectal cancer (Bingham et al., 1996).

Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCAs) constitute a major class of chemical carcinogens present in the environment. When metabolically activated, these compounds act as mutagens and carcinogens in animal models (Culp et al., 1998; Moller et al., 2002; Dingley et al., 2003) and are able to form bulky DNA adducts in humans (Hecht, 2003), (Phillips, 2002) . Many PAHs and HCAs are found to be tumourigenic in humans or experimental animals (International Agency for Research on Cancer (IARC), 1983). Cooking meat at high temperatures and certain preservation and processing procedures leads to the formation of PAHs and HCAs (Sinha et al., 2005; Guillen et al., 1997) . PAHs are ubiquitous environmental contaminants formed by incomplete combustion of organic matter. They are one of several classes of carcinogenic chemicals present in tobacco smoke (Benhamou et al., 2003; Melikian et al., 1999). PAH compounds may not only be formed by high cooking temperatures but are also found in uncooked food, like sea food and plants, due to contamination of the aquatic environment (Meador et al., 1995) or via atmospheric exposure (Guillen et al., 1997).
