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Grant Details

Grant Number: 5R01CA068288-04 Interpret this number
Primary Investigator: O'Neill, James
Organization: University Of Vermont & St Agric College
Project Title: Human Susceptibility to Genetic Damage and Skin Cancer
Fiscal Year: 1998
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Abstract

Humans are exposed to two ubiquitous environmental mutagens inherent in life on earth - gamma irradiation and ultraviolet (UV) light. The biological effects of exposure to these agents included gene mutations and cancer. The human diseases, xeroderma pigmentosum and ataxia telangiectasia, exemplify how reduced DNA repair capacity can lead in an increase in mutations and to a predisposition to cancer. There is increasing evidence that DNA repair capacity, like any phenotypic trait, is heterogeneously distributed among the human population. The large number of genes involved in DNA repair processes results in a distribution Of heterogeneity within the population and predicts that some individuals will have decreased repair capacity. These individuals may be more prone to adverse biological effects of environmental exposures. The goal of this study is to determine the correlation between individual susceptibility to the cytotoxic damage induced by exposure to gamma irradiation and UV light, and their susceptibility to head and neck skin cancer. The study group will be individuals treated with X- irradiation for tinea capitis in childhood (average age eight years) between 1940 and 1959. The risk of these individuals developing basal cell carcinomas (BCC) is greatly increased relative to un-irradiated controls (3.7), especially the incidence of multiple skin cancers (MSC) which is increased to 8.3. The location of the BCC (face and neck which received 4-20% of the total irradiation), the absence of BCC in individuals of Black African descent and a correlation between sun exposure and/or light skin suggests a role for UV light in this cancer progression. We will determine in vivo susceptibility to gamma irradiation and UV light induced cytotoxicity in T-lymphocytes from peripheral blood samples (SA1), and define intra-individual heterogeneity (SA2) and correlation with the incidence of BCC (SA3). We will test the hypothesis that increased susceptibility to cytotoxicity predicts increased cancer susceptibility. Furthermore, we will test the hypothesis that intra-individual, inter-clonal differences in susceptibility due to loss of heterozygosity of DNA repair genes correlates with susceptibility to MsC. This will be determined in isolated T-lymphocyte clones which contain mutations in a reporter gene, hypoxanthine-guanine phosphoribosyltransferase (hprt). Cells which have suffered a mutation in vivo may represent those clonal populations most susceptible to genetic damage (SA4). The long term objective of this study is to better understand the individual's risk for cancer. Individuals with increased susceptibility to the cytotoxic damage induced by gamma irradiation or UV light may be at greatest risk for BCC. This study will determine whether cancer risk can be predicted by this assay for T-lymphocyte sensitivity.

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Publications

DNA damage, DNA repair, cell proliferation, and DNA replication: how do gene mutations result?
Authors: O'Neill J.P. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2000-10-10; 97(21), p. 11137-9.
PMID: 11016974
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Transition mutations at CpG dinucleotides are the most frequent in vivo spontaneous single-based substitution mutation in the human HPRT gene.
Authors: O'Neill J.P. , Finette B.A. .
Source: Environmental and molecular mutagenesis, 1998; 32(2), p. 188-91.
PMID: 9776183
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Metabolic cooperation in the selection of thioguanine-resistant mutants does not occur with the human B-lymphoblastoid cell TK6.
Authors: Gundel R.M. , O'Neill J.P. .
Source: Environmental and molecular mutagenesis, 1997; 30(3), p. 359-61.
PMID: 9366916
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