||5R01CA068288-04 Interpret this number
||University Of Vermont & St Agric College
||Human Susceptibility to Genetic Damage and Skin Cancer
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
DNA damage, DNA repair, cell proliferation, and DNA replication: how do gene mutations result?
Proceedings of the National Academy of Sciences of the United States of America, 2000-10-10; 97(21), p. 11137-9.
Transition mutations at CpG dinucleotides are the most frequent in vivo spontaneous single-based substitution mutation in the human HPRT gene.
, Finette B.A.
Environmental and molecular mutagenesis, 1998; 32(2), p. 188-91.
Metabolic cooperation in the selection of thioguanine-resistant mutants does not occur with the human B-lymphoblastoid cell TK6.
, O'Neill J.P.
Environmental and molecular mutagenesis, 1997; 30(3), p. 359-61.