ATM (ataxia telangiectasia mutated) heterozygosity seems to be a risk factor for cancer. Even though the penetrance seems to be low, because of the high prevalence of 1-5% in the human population, the population risk is higher than for BRCA1 and BRCA2 together. We hypothesize that the reason why only some people heterozygous for ATM develop cancer may in part be due to the fact that the human population is extremely varied with regard to additional genetic cancer predisposing or protecting factors as well as nutrition factors and that only certain gene-gene and/or gene-nutrition interactions may lead to the highest risk for cancer. Genetic instability, in particular DNA deletions are involved in the etiology of cancer. ATM deficient homozygous patients and mice show a high incidence of cancer, signs of oxidative stress and an elevated frequency of DNA deletions which we found using an in vivo pigmentation assay. This assay is based on the quantification of black spots on fur and eyes resulting from reversion of the pun mutation. This reversion occurs by deletion of 70 kb of an internal duplication within the p gene. We have also shown that ATMASRI missense mutation homozygous as well as heterozygous mice show elevated frequencies of DNA deletions. In addition, we have shown that the elevated frequency of DNA deletions in ATM homozygous disruption mutant mice is completely reverted to wildtype levels by nutritional supplementation with the radical scavenger N-acetyl cysteine (NAC). GGT deficient mice have lower levels of glutathione and show signs of oxidative stress.
In aim 1 we propose to investigate whether ATMASRI heterozygous or homozygous mice together with GGT deficiency show synergistically elevated frequencies of DNA deletions (gene-gene interactions), In aim 2 we propose to test whether ATMASRI homo and heterozygous mice nutritionally supplemented with NAC show reduced frequencies of DNA deletions and whether mice supplemented with the prooxidant BSO show an increased frequency of deletions (gene-nutrition interactions). It will be tested in the third aim whether the elevated frequency of cancer in ATMASRI homozygous mice can be reduced by chemoprevention with the antioxidant NAC (gene-nutrition interaction). Implications for human health may include that ATM patients as well as heterozygous people (1-5% of the human population) in combination with genetic or nutritional factors predisposing to a higher sensitivity to oxidative stress may show an increased risk for cancer, and that chemoprevention with antioxidants may reduce the cancer risk in such genetically predisposed people.
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