Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Genotypes, haplotypes and diplotypes of three XPC polymorphisms in urinary-bladder cancer patients
Introduction
The occurrence of urinary bladder cancer, one of the ten most common cancers in the western world, can be influenced by dietary intake and environmental factors e.g. polycyclic aromatic hydrocarbons and polychlorinated biphenyls [1], [2], [3]. Many chemical carcinogens form bulky DNA adducts after activation by various metabolic enzymes [4], [5]. These bulky adducts are in general removed by a multi-step nucleotide excision repair (NER) pathway [6]. Un-repaired DNA damage, due to defective NER, can lead to mis-incorporation of bases at the damaged sites, fixation of mutations and ultimately cancer [7]. Molecular epidemiological studies have shown considerable inter-individual variations in the DNA repair capacity in the general population which could partially stem from the genetic polymorphisms in genes involved in the repair processes. Therefore, it has been postulated that inherited polymorphisms in NER genes can modulate the susceptibility to cancer in the general population.
The xeroderma pigmentosum group C (XPC) protein has a vital function in the repair process of potential carcinogenic lesions. The protein binds to RAD23B (also known as HR23B) and plays a key role in damage detection and initiating NER [8]. The XPC gene spans 33 kb on chromosome 3 and contains 16 exons and 15 introns, encoding a 940 amino acid protein [9]. Germ line mutations in the XPC gene result in defective NER, and are associated with the Xeroderma pigmentosum syndrome, complementation group C. Beside mutations, several polymorphisms in this gene have been reported (listed in e.g. http://snp500cancer.nci.nih.gov/home.cfm) [10], [11]. Although the functional effects of these polymorphisms have not yet been fully elucidated, it is plausible that genotypes, haplotypes and diplotypes of some of these polymorphisms may have an effect on NER capacity, thereby modulating the risk of cancer.
In two previous studies we reported an association of bladder cancer with the variant allele of the A499V (C > T, rs2228000) and the K939Q (A > C, rs2228001) polymorphisms in the XPC gene [12], [13]. In the present study we extended these analysis and also investigated the poly AT polymorphism (PAT −/+) of XPC [11]. In addition we studied linkage disequilibrium (LD) between the A499V (C > T), K939Q (A > C) and PAT (−/+) polymorphic loci and investigated the association of the three polymorphisms in XPC with urinary-bladder cancer with regards to allele frequencies, genotypes, haplotypes and diplotypes.
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Subjects
Our study group was drawn from a population-based patient material consisting of 78% (563/721) of all newly diagnosed bladder-cancer patients 1995–1996 in the Stockholm County, Sweden [14]. Venous blood was collected at a later time point and was available for 311 patients of Caucasian origin (201 men, 94 women and 16 unknown), which were included in the present study. DNA was extracted from blood as described previously [15]. Tumor stage was assessed according to a modified TNM system by Hall
Association of genotype and allele frequencies of XPC polymorphisms and bladder cancer
The frequencies of the variant allele genotypes (CT and TT) and variant allele (T) of the A499V (C > T) polymorphism were significantly higher in the cases than controls (Table 1). We found a six-fold increased odds ratio for the variant allele homozygotes (p < 0.0001) when compared to common allele homozygotes (Table 1). The frequency of the K939Q (A > C) variant allele homozygous CC genotype was also significantly higher in the urinary-bladder cancer cases than in population controls. This study
Discussion
DNA damages induced by occupational exposure to chemicals and smoking are well known risk factors for bladder cancer. The XPC protein is crucial in the recognition and initiation of the nucleotide excision pathway (NER), which eliminates a wide variety of DNA damages induced by chemical and environmental exposures such as aromatic amines and UV light. Polymorphisms in the XPC gene have been shown to influence an individual's DNA repair capacity, and hence it is plausible that genetic variation
Conflict of interest
None.
Acknowledgement
Grants were obtained from the Swedish Cancer Association (Cancerfonden CAN2007/649), the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet (ALF), Magnus Bergvall's Foundation and the Foundation in Memory of Johanna Hagstrand and Sigfrid Linnér.
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