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Title: Nucleotide excision repair gene polymorphism and skin cancer
Author: Tomeson, D.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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The most important environmental risk factor for skin cancer is sunlight exposure. The genetic component is seen in the inherited genodermatoses, such as Xeroderma Pigmentosum (XP), where there is a 1000-fold increased risk of skin cancer. Nucleotide excision repair (NER), the pathway responsible for removal of UV-induced DNA damage, is defective in XP patients. The XPB and XPD helicases are essential components of the NER pathway. Frequent polymorphisms have been reported in NER genes and polymorphisms in ERCC2, ERCC1 and XPF have been investigated for association with various types of cancer, including melanoma, non-melanoma skin cancer and cancers of lung, brain, bladder. My study investigated the possibility of an association between two NER genes (XPB and XPD) and melanoma in a case control study on 28 cases and 33 controls. The study addressed the hypothesis that polymorphisms in NER genes leading to altered proteins might be a cancer risk factor because of altered interactions between repair proteins and the cell cycle control machinery. No variation was found in the XPB gene. Most of the 23 exons from the XPD gene have been screened and sequence variation has been observed in exons 6, 22, 23, 18 and 20. Analysis of the polymorphisms in exon 6, 22 and 23 showed that, in each case, one allele was over-represented in the melanoma group. The exon 6 (156Arg) and exon 22 (711Asp) changes were silent while the exon 23 change altered the protein sequence (Lys751Gln). The association did not extend to the closest flanking markers, suggesting that susceptibility to melanoma might be located within the XPD gene itself. Control human lymphocyte cultures with different exon 23 genotypes were studied to investigate the possibility that the XPD exon 23 alleles might interact differently with p53 to effect the response to UV-induced DNA damage. These was no association between the strength of the p53 response and the Lys751Gln polymorphism. These findings need confirmation from a larger study group and from additional functional assays.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available