The mutated ataxia telangiectasia (AT) gene causes a distinctive neurological, immunological and cancer-prone syndromes in homozygotes. Heterozygous carriers of this gene constitute about 1 percent of the general population. The principal investigator and others have generated data that support the hypothesis that these heterozygous carriers are predisposed to breast and other cancers. Prospective clinical data will be continued to be collected from blood relatives in approximately 266 AT families already participating in this study. These will be incorporated with their own detailed retrospective health and mortality data. DNA samples will be collected for as many relatives as possible. The specific AT mutations segregating in these families will be determined as a basis for eventual population-based studies, to evaluate the role of different mutations in disease predisposition, and for use in this study. The AT gene carrier status of each participating relative will be determined through linked haplotypes or direct mutation detection. The excess mortality and disease risk of AT heterozygotes compared to non-carriers will be evaluated by rate ratio analysis of the prospective mortality and disease incidence rates. The statistically powerful unbiased index-test method will be used to estimate the relative risk of the AT heterozygote for specific cancers and ischemic heart disease. The role of environmental factors such as ionizing radiation and smoking will be examined through nested case-control studies. New measures to reduce the mortality and excess disease incidence of AT heterozygotes will be developed based upon the findings of this study.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA014235-24A1
Application #
2007164
Study Section
Special Emphasis Panel (ZRG2-BIOL-1 (04))
Project Start
1976-06-30
Project End
1999-12-31
Budget Start
1997-05-15
Budget End
1997-12-31
Support Year
24
Fiscal Year
1997
Total Cost
Indirect Cost
Name
New York Medical College
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Schroeder, Scott A; Swift, Michael; Sandoval, Claudio et al. (2005) Interstitial lung disease in patients with ataxia-telangiectasia. Pediatr Pulmonol 39:537-43
Sandoval, Claudio; Swift, Michael (2003) Hodgkin disease in ataxia-telangiectasia patients with poor outcomes. Med Pediatr Oncol 40:162-6
Su, Y; Swift, M (2000) Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med 133:770-8
Li, A; Swift, M (2000) Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am J Med Genet 92:170-7
Li, A; Huang, Y; Swift, M (1999) Neutral sequence variants and haplotypes at the 150 Kb ataxia-telangiectasia locus. Am J Med Genet 86:140-4
Weissberg, J B; Huang, D D; Swift, M (1998) Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes. Int J Radiat Oncol Biol Phys 42:1133-6
Athma, P; Rappaport, R; Swift, M (1996) Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 92:130-4
Athma, P; Fidahusein, N; Swift, M (1995) Single base polymorphism linked to the ataxia-telangiectasia locus is detected by mismatch PCR. Biochem Biophys Res Commun 210:982-6
Athma, P; Liu, J; Swift, M (1995) PCR detection of the Taq1 restriction fragment length polymorphism linked to the ataxia telangiectasia locus. Clin Chem 41:625-6
Lench, N J; Athma, P; Ottaiano, A et al. (1994) DNA marker D11S384 shows zero recombination with the ataxia-telangiectasia locus in North American families. Int J Radiat Biol 66:S67-9

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