Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms, interactions with smoking, alcohol and dietary factors, and risk of colorectal cancer
Introduction
Colorectal cancer is the third most common cancer and the leading cause of cancer deaths in western industrialised countries. The nucleotide excision repair (NER) pathway is the primary mechanism for removal of bulky adducts from DNA, and thus is an important part of the cellular defence against a large variety of structural unrelated DNA lesions. If these DNA lesions are left unrepaired, they may contribute to mutagenesis and oncogenesis.
XPA and XPC enzymes are involved in the damage recognition-complex of NER. Several studies have shown the XPC-hHR23B complex to function at a very early stage of DNA damage recognition [1], [2], [3], [4], why XPC is thought to be the initiator in global genomic NER. By interaction with the XPC complex XPA, the transcription repair factor TFIIH and other repair factors may be recruited to the damaged DNA site [2], [4]. XPA is capable of interacting with TFIIH [5], and binding to the XPF-ERCC1 complex with very high affinity [6]. Hence, it is thought to be crucial to the subsequent positioning of the involved NER enzymes. The variant allele of the polymorphism XPC Lys939Gln may be associated with high risk of bladder cancer [7] and lung cancer [8], and a lowered risk of endometrial cancer [9]. In a Korean population carriers of the variant allele in the XPA A23G polymorphism, located at position-4 from the ATG start codon [10], were reported to have a 1.7-fold higher risk of lung cancer among homozygous carriers of the variant A-allele compared to carriers of the wild type allele [11]. Studies on lung cancer risk in Caucasians also indicate a tendency of a higher risk among carriers of the variant A-allele [8], [12], with an OR of 1.72 (CI: 0.95–3.13) for homozygous carriers [8]. Weiss et al. observed a decreased risk of endometrial cancer among carriers of the variant A-allele [9]. We know of no studies of the effect of the XPA and XPC polymorphisms in relation to colorectal cancer.
XPD encodes a helicase that participates in the unwinding of helix in the region of damaged DNA [1]. The variant alleles of the polymorphisms XPD Asp312Asn and XPD Lys751Gln have been associated with increased DNA adduct levels [13], [14], [15], and with low DNA repair capacity [16]. No association has been observed between the XPD Lys751Gln polymorphism to risk of colorectal carcinoma [17], [18], [19], [20], but a recent Norwegian study detected an association with risk of colorectal adenomas [17]. In several studies, carriers of the variant allele of XPD Lys751Gln and XPD Asp312Asn were found to be at higher risk of lung cancer [21], [22], [23], whereas other studies did not find this association [24], [25]. The polymorphisms have not been associated to risk of basal cell carcinoma [26] or bladder cancer [27].
Our current knowledge of colorectal carcinogenesis indicates a multi-factorial and multi-step process that involves various genetic alterations and several biological pathways. Thus, it is unlikely that risk factors of colorectal cancer work in isolation from each other. The variant alleles of XPA A23G [12], XPD Asp312Asn and XPD Lys751Gln [16], [28] polymorphisms and a polymorphism in XPC [28], in full linkage disequilibrium with the XPC Lys939Gln polymorphism [29], have been associated with a lowered DNA repair capacity compared to the wild type allele. Therefore, we hypothesized that interaction between the four polymorphisms and exposure of environmental risk factors able to cause bulky DNA lesions may possibly exist, in relation to risk of colorectal cancer.
Several epidemiological studies have shown that consumption of some dietary constituents, e.g. red or processed meat, fat and alcohol, are associated with increased risk of colorectal cancer, whereas other dietary constituents, e.g. fish, dietary fibre, fruit and vegetables, may be associated with a decreased risk [30], [31], [32], but the epidemiological data are not entirely consistent. An association between tobacco smoking and risk of colorectal cancer has not been established.
Intake of red meat and meat cooked at high temperatures has previously been suggested to be associated with an increased risk of colorectal adenoma [33]. Whether the risk is related to high intake of red meat per se or to meat cooking-practices is unclear. Cooking meat at high temperatures leads to the formation of polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) [33]. When metabolically activated, these compounds act as mutagens and carcinogens in animal models [34], [35], [36] and are able to form bulky DNA adducts in humans (reviewed by [37] and [38]). High intake of red meat was associated with higher risk of colorectal cancer in eight studies in a meta-analysis by Sandhu et al. [39]. Higher levels of DNA-PAH DNA adducts in white blood cells [40], [41] and in human colon mucosa [42] has been reported in subjects with high intake of the PAH benzo[a]pyrene (BaP) from grilled meat and/or tobacco use. Intake of BaP has also been associated to an increased risk of colorectal adenomas [43], [44]. Intake of red meat may increase the formation of DNA damaging N-nitrosocompounds (NOCs) [45], [46], [47] with potential of DNA adduct formation. Such adducts have been detected in human blood DNA samples in individuals who had consumed a diet rich of meat [46].
Many chemical carcinogens have been detected in cigarette smoke such as PAHs, aromatic amines, and nitrosamines [48]. Following tobacco smoking, adducts formed by metabolites of these compounds are not only located in airway tissue, but are also found in, e.g. bladder and cervical tissue from smokers [49], [50].
Acetaldehyde is the primary oxidative metabolite of ethanol. Exposure of DNA to acetaldehyde can result in various lesions, the most studied DNA lesion being N2-ethyl-2′-deoxyguanosine. Acetaldehyde and malondialdehyde can combine to form the malondialdehyde–acetaldehyde (MAA) adduct, which is very reactive and avidly binds to DNA [51]. Ethanol supplementation in the drinking water has been demonstrated to increase intestinal tumorigenesis in multiple intestinal neoplasia (MIN) mice, the potential mechanism being formation of mutagenic MAA DNA adducts [52]. Fang and Vaca conducted a study with alcoholic patients and control subjects measuring the level of acetaldehyde DNA adducts in white blood cell DNA. The adduct levels in the alcohol abusers were statistically significantly higher, up to 13-fold, than in subjects from the non-drinking control group [53].
Intake of fruit, vegetables and fish are reported to be negatively associated with DNA adduct levels [54], [55], although some studies found no effect [56], [57].
To our knowledge, only very few studies have investigated the association between the XPD Lys751Gln and XPD Asp312Asn polymorphisms and risk of colorectal cancer. We know of no reports on the relationship of XPA A23G and XPC Lys939Gln polymorphisms with risk of colorectal cancer, or on the interactions between the four polymorphisms and environmental risk factors. In the present study we wished to determine the risk of colorectal cancer in association with the XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms and interactions between the polymorphisms and the environmental factors: smoking intensity, intake of alcohol, red and processed meat, fish and poultry, fruits and vegetables and dietary fibres, in the development of colorectal cancer.
Section snippets
Study group
Diet, Cancer and Health (DCH) is a Danish prospective follow-up study. A population of 160,725 individuals aged 50–64 years and born in Denmark, were invited to participate, of which 57,053 individuals with no previous cancer diagnosis were recruited [58]. At enrolment in 1993–1997, detailed information on diet, smoking habits, lifestyle, weight, height, reproduction, and medical treatment and other socio-economic characteristics and environmental exposures were collected. The participants were
Results
Forty-five percent of the cases were diagnosed with rectal cancer, 52% with colon cancer, and for 3% the topography was not specified. Among cases, 96% had a diagnosis of adenocarcinomas, 2% of carcinoid tumor and 2% of various other histological subtypes. The distribution of cancer location was comparable for men and women, data not shown. The median follow-up time was 6.7 years. BMI and use of hormone replacement therapy (HRT) was similar between cases and members of the sub-cohort. The level
Discussion
We found no support for the hypothesis that risk of colorectal cancer is associated with the XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms. Even though Danes probably have a high environmental exposure to PAHs, HCAs and NOCs due to their relatively high intake of alcohol [67] and red and processed meat [68] compared to other European countries, and a high percentage of smokers, we were only able to detect one statistically significant gene–environment interaction: The
Acknowledgements
We thank Anne-Karin Jensen, Lourdes M. Pedersen and Yonit M. Bertelsen for excellent technical assistance. This study was supported by Danish Research Council (Grant number 2052-03-0016) and a scholarship from the Danish Graduate School in Public Health Science and from the Faculty of Medicine at University of Copenhagen.
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