**3.2.4** *ERCC1* **Asn118Asn**

The results from studies by Skjelbred *et al*. (Skjelbred et al., 2006a) , Joshi *et al*. (Joshi et al., 2009) , and our Danish study (Hansen et al., 2008) on the *ERCC1* Asn118Asn polymorphism suggest no association with risk of colorectal cancer.

Moreno *et al*. examined five polymorphisms in the *ERCC1* gene. A haplotype containing the minor allele of three of the *ERCC1* polymorphisms was associated with a higher risk of colorectal cancer (OR=2.3, 95% CI: 1.0-5.3) compared with carriers of the most frequent haplotype (Moreno et al., 2006). Two other SNPs in the *ERCC1* gene were not associated with risk of colorectal cancer (Mort et al., 2003; Berndt et al., 2006).

#### **3.3 SNPs in NER and risk of other types of cancer than colorectal cancer**

Numerous association studies of polymorphisms in genes involved in NER are reported on various types of cancer, with the majority of studies focused on the *XPD* Lys751Gln and *XPD* Asp312Asn polymorphisms. A meta-analysis of lung cancer by Kiyohara *et al.* (with 1913 cases and 1882 controls of different ethnicities) (Kiyohara & Yoshimasu, 2007) suggested among other studies (Xing et al., 2002; Hu et al., 2004; Yin et al., 2006), that carriers of the variant alleles of either of the two *XPD* polymorphisms were found to be at higher risk of lung cancer, while a number of other studies did not observe any association of the two polymorphisms with lung cancer risk (De et al., 2007; Vogel et al., 2005b; Popanda et al., 2004; Hu et al., 2006).


Polymorphisms in Nucleotide Excision Repair

Genes and Risk of Colorectal Cancer: A Systematic Review 549

Table 2. Studies of possible associations between polymorphisms in *XPD*, *XPA*, *XPC,* and *ERCC1* and risk of colorectal adenomas or colorectal cancer and gene-environment (G E) interaction on risk of colorectal adenomas or colorectal cancer. The results reviewed and included are solely on polymorphisms in the four genes and the environmental factors that are the topic of the present book chapter.


Table 2. Studies of possible associations between polymorphisms in *XPD*, *XPA*, *XPC,* and *ERCC1* and risk of colorectal adenomas or colorectal cancer and gene-environment (G E) interaction on risk of colorectal adenomas or colorectal cancer. The results reviewed and included are solely on polymorphisms in the four genes and the environmental factors that are the topic of the present book chapter.

548 DNA Repair

Polymorphisms in Nucleotide Excision Repair

al., 2006).

results are inconsistent.

satisfactorily clarified at present.

**4. Discussion** 

Genes and Risk of Colorectal Cancer: A Systematic Review 551

Hu et al., 2006): Individuals with both putative genotypes of *XPC* Lys939Gln and *XPC* Ala499Val polymorphisms are observed with a 2.4-fold (OR=2.37, CI: 1.33-4.21) higher risk of lung cancer compared with individuals with both wild type genotypes (Vogel et al., 2005b; Lee et al., 2005; Hu et al., 2006), with the higest risk observed among smokers. Polymorphisms in *XPC* have not been associated to risk of basal cell carcinoma (Festa et al., 2005; Nelson et al., 2005), cutaneous melanoma (Blankenburg et al., 2005; Li et al., 2006a) or breast cancer (Mechanic et al., 2006; Jorgensen et al., 2007; Forsti et al., 2004). A lower risk of endometrial cancer may be associated with carriage of at least one variant allele for both

In a Korean population carriers of the wild type allele (G/G or A/G) in the *XPA* G23A polymorphism were reported to have a lower risk of lung cancer compared to carriers of the A/A genotype, with an OR of 0.56 (CI:0.35-0.90) (Park et al., 2002). Similar results were obtained in studies on lung cancer risk in Caucasians and Mexican-Americans (Vogel et al., 2005b; Wu et al., 2003) (Popanda et al., 2004), while a Norwegian study observed the inverse effect with a 1.6-fold higher risk (OR=1.59, CI:1.12-2.27) of lung cancer among carriers of the G/G genotype compared with carriers of the A-allele (Zienolddiny et al., 2006). When stratifying by smoking status the protective effect for lung cancer was only observed among ever smokers (Wu et al., 2003) or current smokers (Park et al., 2002) carrying at least one Gallele or the G/G genotype, respectively. A tendency for lower risk of basal cell carcinoma has been observed among carriers of the variant G-allele, with an OR of 0.82 (CI: 0.66-1.01) and an OR of 0.74 (CI: 0.53-1.03) for homozygous and heterozygous carriers, respectively (Miller et al., 2006). The same tendency was observed for risk of squamous cell carcinoma (Miller et al., 2006). Carriage of at least one A-allele for *XPA* G23A was associated with decreased risk of endometrial cancer, OR=0.47 (CI:0.25-0.82) compared with carriers of the G/G genotype, but only among women with a history of using oral contraceptives (Weiss et

The *ERCC1* Asn118Asn polymorphism is not associated with testicular cancer (Laska et al., 2005). Furthermore, no association has been observed for the *ERCC1* Asn118Asn polymorphism to risk of endometrial cancer (Jo et al., 2007; Weiss et al., 2006), ovarian

All in all the studies suggest that the two *XPD* polymorphisms at amino acid position 312 or 751, the *XPD* Lys751Gln in particular, are associated with risk of cancer in the lung, breast and bladder and seems to modify the effect of smoking on risk of the three cancer forms. The *XPC* Lys939Gln polymorphism may possibly be associated with risk of bladder cancer, and the *XPA* G23A polymorphism may be associated with risk of skin cancer (basal cell carcinoma), endometrial cancer and lung cancer. However, the studies are few and the

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

cancer (Jo et al., 2007) and adult glioma (Wrensch et al., 2005).

*XPC* Lys939Gln and *XPC* Ala499Val polymorphisms (Weiss et al., 2005).

Two large meta-analyses (with 3725 cases and 4152 controls) included identical nine casecontrol studies but made two dissimilar conclusions: The *XPD* Lys751Gln and *XPD* Asp312Asn polymorphisms are associated with risk of lung cancer (Hu et al., 2004) or no clear association was found (Benhamou & Sarasin, 2005). Some studies suggest an interaction between the two *XPD* polymorphisms and smoking in relation to risk of lung cancer (De et al., 2007; Hu et al., 2006; Xing et al., 2002).

Combinations of the *XPD*, *XPC* and *XPA* genotypes, variant alleles, is suggested to be associated with higher risk of lung cancer (Vogel et al., 2005b). This may be plausible but in the light of multiple testing and the low number of cases this may be a chance finding. The largest breast cancer studies by the number of individuals, 1053 cases/1102 controls (Terry et al., 2004) and 1830 cases/1262 controls (Debniak et al., 2006) observed modest associations of the *XPD* polymorphisms with breast cancer risk. Carriers of the variant *XPD* Lys751Gln allele was associated with a 20% higher risk (OR=1.21, CI: 1.01-1.44) compared with homozygous carriers of the wild type allele. The risk seemed limited to those with a PAH-DNA adduct level above the median, with an OR of 1.61 (CI: 0.99-2.63) among homozygous carriers of the *XPD* 751Gln allele (Terry et al., 2004). Several other studies observed no association of the *XPD* Lys751Gln polymorphism (Debniak et al., 2006; Dufloth et al., 2005; Brewster et al., 2006; Costa et al., 2007; Mechanic et al., 2006; Jorgensen et al., 2007) or the *XPD* Asp312Asn polymorphism (Mechanic et al., 2006; Forsti et al., 2004)to risk of breast cancer. However, higher risk has been detected among ever smoking women carrying the *XPD* 751Gln allele (OR=2.52, CI: 1.27-5.03) compared to ever smoking women carrying the homozygous wild type allele (Metsola et al., 2005). Association with breast cancer risk has been detected when the homozygous variant *XPD* Lys751Gln allele and the homozygous variant *XPD* Asp312Asn allele segregated together, with OR=1.5 (p<0.05) and OR=3.69 (CI: 1.76-7.74), respectively (Debniak et al., 2006; Justenhoven et al., 2004). A large study including 2485 cases with single primary melanoma and 1238 cases with second or higher order primary melanomas detected higher melanoma risk among homozygous carriers of the variant *XPD* Lys751Gln allele (OR=1.4, CI: 1.1-1.7) or the variant *XPD* Asp312Asn allele (OR=1.5, CI: 1.2-1.9), respectively (Millikan et al., 2006). Similar results were obtained in a study by Li *et al*. (Li et al., 2006b), while another study observed the inverse association for both polymorphisms (Han et al., 2005). When stratifying by age Baccarelli *et al.* observed an association of the two *XPD* polymorphisms to risk of melanoma only among the individuals older than 50 years when diagnosed (Baccarelli et al., 2004). The *XPD* Lys751Gln (Andrew et al., 2006) and the *XPD* Asp312Asn polymorphism (Wu et al., 2006) have been associated with risk of bladder cancer. An interaction is suggested between the *XPD* Lys751Gln polymorphism and smoking in relation to bladder cancer risk (Andrew et al., 2006; Stern et al., 2002; Schabath et al., 2005). Individuals carrying both the variant *XPD* alleles were more susceptible to development of bladder cancer (Wu et al., 2006; Andrew et al., 2006) than carriers of wild type alleles. The *XPD* Lys751Gln and *XPD* Asp312Asn polymorphisms have not been associated to risk of basal cell carcinoma (Vogel et al., 2005a; Festa et al., 2005; Han et al., 2005; Lovatt et al., 2005), endometrial cancer (Weiss et al., 2006) prostate cancer (Ritchey et al., 2005) or gastric cancer (Huang et al., 2005).

A small study suggest that the variant allele of the polymorphism XPC Lys939Gln is associated with higher risk of bladder cancer (OR=1.49, CI:1.16-1.92) (Sanyal et al., 2004). No association is observed between the polymorphism and risk of lung cancer (Vogel et al., 2005b; Lee et al., 2005; Hu et al., 2006) but a haplotype encompassing more polymorphisms in *XPC* may contribute to a higher risk of lung cancer (Vogel et al., 2005b; Lee et al., 2005;

Two large meta-analyses (with 3725 cases and 4152 controls) included identical nine casecontrol studies but made two dissimilar conclusions: The *XPD* Lys751Gln and *XPD* Asp312Asn polymorphisms are associated with risk of lung cancer (Hu et al., 2004) or no clear association was found (Benhamou & Sarasin, 2005). Some studies suggest an interaction between the two *XPD* polymorphisms and smoking in relation to risk of lung

Combinations of the *XPD*, *XPC* and *XPA* genotypes, variant alleles, is suggested to be associated with higher risk of lung cancer (Vogel et al., 2005b). This may be plausible but in the light of multiple testing and the low number of cases this may be a chance finding. The largest breast cancer studies by the number of individuals, 1053 cases/1102 controls (Terry et al., 2004) and 1830 cases/1262 controls (Debniak et al., 2006) observed modest associations of the *XPD* polymorphisms with breast cancer risk. Carriers of the variant *XPD* Lys751Gln allele was associated with a 20% higher risk (OR=1.21, CI: 1.01-1.44) compared with homozygous carriers of the wild type allele. The risk seemed limited to those with a PAH-DNA adduct level above the median, with an OR of 1.61 (CI: 0.99-2.63) among homozygous carriers of the *XPD* 751Gln allele (Terry et al., 2004). Several other studies observed no association of the *XPD* Lys751Gln polymorphism (Debniak et al., 2006; Dufloth et al., 2005; Brewster et al., 2006; Costa et al., 2007; Mechanic et al., 2006; Jorgensen et al., 2007) or the *XPD* Asp312Asn polymorphism (Mechanic et al., 2006; Forsti et al., 2004)to risk of breast cancer. However, higher risk has been detected among ever smoking women carrying the *XPD* 751Gln allele (OR=2.52, CI: 1.27-5.03) compared to ever smoking women carrying the homozygous wild type allele (Metsola et al., 2005). Association with breast cancer risk has been detected when the homozygous variant *XPD* Lys751Gln allele and the homozygous variant *XPD* Asp312Asn allele segregated together, with OR=1.5 (p<0.05) and OR=3.69 (CI: 1.76-7.74), respectively (Debniak et al., 2006; Justenhoven et al., 2004). A large study including 2485 cases with single primary melanoma and 1238 cases with second or higher order primary melanomas detected higher melanoma risk among homozygous carriers of the variant *XPD* Lys751Gln allele (OR=1.4, CI: 1.1-1.7) or the variant *XPD* Asp312Asn allele (OR=1.5, CI: 1.2-1.9), respectively (Millikan et al., 2006). Similar results were obtained in a study by Li *et al*. (Li et al., 2006b), while another study observed the inverse association for both polymorphisms (Han et al., 2005). When stratifying by age Baccarelli *et al.* observed an association of the two *XPD* polymorphisms to risk of melanoma only among the individuals older than 50 years when diagnosed (Baccarelli et al., 2004). The *XPD* Lys751Gln (Andrew et al., 2006) and the *XPD* Asp312Asn polymorphism (Wu et al., 2006) have been associated with risk of bladder cancer. An interaction is suggested between the *XPD* Lys751Gln polymorphism and smoking in relation to bladder cancer risk (Andrew et al., 2006; Stern et al., 2002; Schabath et al., 2005). Individuals carrying both the variant *XPD* alleles were more susceptible to development of bladder cancer (Wu et al., 2006; Andrew et al., 2006) than carriers of wild type alleles. The *XPD* Lys751Gln and *XPD* Asp312Asn polymorphisms have not been associated to risk of basal cell carcinoma (Vogel et al., 2005a; Festa et al., 2005; Han et al., 2005; Lovatt et al., 2005), endometrial cancer (Weiss et al., 2006) prostate cancer

cancer (De et al., 2007; Hu et al., 2006; Xing et al., 2002).

(Ritchey et al., 2005) or gastric cancer (Huang et al., 2005).

A small study suggest that the variant allele of the polymorphism XPC Lys939Gln is associated with higher risk of bladder cancer (OR=1.49, CI:1.16-1.92) (Sanyal et al., 2004). No association is observed between the polymorphism and risk of lung cancer (Vogel et al., 2005b; Lee et al., 2005; Hu et al., 2006) but a haplotype encompassing more polymorphisms in *XPC* may contribute to a higher risk of lung cancer (Vogel et al., 2005b; Lee et al., 2005; Hu et al., 2006): Individuals with both putative genotypes of *XPC* Lys939Gln and *XPC* Ala499Val polymorphisms are observed with a 2.4-fold (OR=2.37, CI: 1.33-4.21) higher risk of lung cancer compared with individuals with both wild type genotypes (Vogel et al., 2005b; Lee et al., 2005; Hu et al., 2006), with the higest risk observed among smokers. Polymorphisms in *XPC* have not been associated to risk of basal cell carcinoma (Festa et al., 2005; Nelson et al., 2005), cutaneous melanoma (Blankenburg et al., 2005; Li et al., 2006a) or breast cancer (Mechanic et al., 2006; Jorgensen et al., 2007; Forsti et al., 2004). A lower risk of endometrial cancer may be associated with carriage of at least one variant allele for both *XPC* Lys939Gln and *XPC* Ala499Val polymorphisms (Weiss et al., 2005).

In a Korean population carriers of the wild type allele (G/G or A/G) in the *XPA* G23A polymorphism were reported to have a lower risk of lung cancer compared to carriers of the A/A genotype, with an OR of 0.56 (CI:0.35-0.90) (Park et al., 2002). Similar results were obtained in studies on lung cancer risk in Caucasians and Mexican-Americans (Vogel et al., 2005b; Wu et al., 2003) (Popanda et al., 2004), while a Norwegian study observed the inverse effect with a 1.6-fold higher risk (OR=1.59, CI:1.12-2.27) of lung cancer among carriers of the G/G genotype compared with carriers of the A-allele (Zienolddiny et al., 2006). When stratifying by smoking status the protective effect for lung cancer was only observed among ever smokers (Wu et al., 2003) or current smokers (Park et al., 2002) carrying at least one Gallele or the G/G genotype, respectively. A tendency for lower risk of basal cell carcinoma has been observed among carriers of the variant G-allele, with an OR of 0.82 (CI: 0.66-1.01) and an OR of 0.74 (CI: 0.53-1.03) for homozygous and heterozygous carriers, respectively (Miller et al., 2006). The same tendency was observed for risk of squamous cell carcinoma (Miller et al., 2006). Carriage of at least one A-allele for *XPA* G23A was associated with decreased risk of endometrial cancer, OR=0.47 (CI:0.25-0.82) compared with carriers of the G/G genotype, but only among women with a history of using oral contraceptives (Weiss et al., 2006).

The *ERCC1* Asn118Asn polymorphism is not associated with testicular cancer (Laska et al., 2005). Furthermore, no association has been observed for the *ERCC1* Asn118Asn polymorphism to risk of endometrial cancer (Jo et al., 2007; Weiss et al., 2006), ovarian cancer (Jo et al., 2007) and adult glioma (Wrensch et al., 2005).

All in all the studies suggest that the two *XPD* polymorphisms at amino acid position 312 or 751, the *XPD* Lys751Gln in particular, are associated with risk of cancer in the lung, breast and bladder and seems to modify the effect of smoking on risk of the three cancer forms. The *XPC* Lys939Gln polymorphism may possibly be associated with risk of bladder cancer, and the *XPA* G23A polymorphism may be associated with risk of skin cancer (basal cell carcinoma), endometrial cancer and lung cancer. However, the studies are few and the results are inconsistent.
