Patients who are homozygous for ataxia-telangiectasia have an exceptionally high incidence of cancer. In a group of families expected to have a high proportion of heterozygotes for ataxia-telangiectasia, we tested the hypothesis that such heterozygotes, estimated to make up 0.68 to 7.7 percent of the U.S. white population, also have an excess cancer risk. Retrospective cancer incidence rates in adult blood relatives of patients with ataxia-telangiectasia in 110 white non-Amish families were significantly elevated over the incidence rates in spouse controls (rate ratios, 1.6 for men [P = 0.032]; 2.0 for women [P = 0.013]). For persons who are heterozygous for ataxia-telangiectasia, the relative risk of cancer was estimated to be 2.3 for men (P = 0.014) and 3.1 for women (P = 0.004). Breast cancer in women was the cancer most clearly associated with heterozygosity for ataxia-telangiectasia (rate ratio, 3.0 [P = 0.028]; heterozygote relative risk, 6.8 [P = 0.006]). On the basis of this estimated relative risk of 6.8 and an estimated heterozygote frequency in the general population of 1.4 percent, 8.8 percent of patients with breast cancer in the U.S. white population would be heterozygous for ataxia-telangiectasia. We conclude that heterozygous carriers of the gene for ataxia-telangiectasia have an excess risk of cancer, particularly breast cancer in women.
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[Abstract][Full Text]
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63: 3325-3333
[Abstract][Full Text]
Evans, D G R, Lalloo, F
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39: 865-871
[Abstract][Full Text]
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[Abstract][Full Text]
Yuille, M. R., Condie, A., Hudson, C. D., Bradshaw, P. S., Stone, E. M., Matutes, E., Catovsky, D., Houlston, R. S.
(2002). ATM mutations are rare in familial chronic lymphocytic leukemia. Blood
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[Abstract][Full Text]
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(2002). Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J. Med. Genet.
39: 225-242
[Abstract][Full Text]
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(2002). ATM mutations in Finnish breast cancer patients. J. Med. Genet.
39: 192-196
[Full Text]
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(2002). Dominant Negative ATM Mutations in Breast Cancer Families. JNCI J Natl Cancer Inst
94: 205-215
[Abstract][Full Text]
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(2001). The Aspergillus nidulans musN Gene Encodes a RecQ Helicase That Interacts With the PI-3K-Related Kinase UVSB. Genetics
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[Abstract][Full Text]
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(2001). Spectrum of ATM Gene Mutations in a Hospital-based Series of Unselected Breast Cancer Patients. Cancer Res.
61: 7608-7615
[Abstract][Full Text]
Smilenov, L. B., Brenner, D. J., Hall, E. J.
(2001). Modest Increased Sensitivity to Radiation Oncogenesis in ATM Heterozygous versus Wild-Type Mammalian Cells. Cancer Res.
61: 5710-5713
[Abstract][Full Text]
Boultwood, J
(2001). Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J. Clin. Pathol.
54: 512-516
[Abstract][Full Text]
Nathanson, K. L., Weber, B. L.
(2001). 'Other' breast cancer susceptibility genes: searching for more holy grail. Hum Mol Genet
10: 715-720
[Abstract][Full Text]
Swift, M.
(2001). Public Health Burden of Cancer in Ataxia-Telangiectasia Heterozygotes. JNCI J Natl Cancer Inst
93: 84-85
[Full Text]
Olsen, J. H., Hahnemann, J. M., Borresen-Dale, A.-L., Brondum-Nielsen, K., Hammarstrom, L., Kleinerman, R., Kaariainen, H., Lonnqvist, T., Sankila, R., Seersholm, N., Tretli, S., Yuen, J., Boice, J. D. Jr., Tucker, M.
(2001). Cancer in Patients With Ataxia-Telangiectasia and in Their Relatives in the Nordic Countries. JNCI J Natl Cancer Inst
93: 121-127
[Abstract][Full Text]
Beales, P. L., Reid, H. A.S., Griffiths, M. H., Maher, E. R., Flinter, F. A., Woolf, A. S.
(2000). Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome. Nephrol Dial Transplant
15: 1977-1985
[Abstract][Full Text]
Su, Y., Swift, M.
(2000). Mortality Rates among Carriers of Ataxia-Telangiectasia Mutant Alleles. ANN INTERN MED
133: 770-778
[Abstract][Full Text]
Martin, A.-M., Weber, B. L.
(2000). Genetic and Hormonal Risk Factors in Breast Cancer. JNCI J Natl Cancer Inst
92: 1126-1135
[Abstract][Full Text]
Emilien, G., Ponchon, M., Caldas, C., Isacson, O., Maloteaux, J.-M.
(2000). Impact of genomics on drug discovery and clinical medicine. QJM
93: 391-423
[Abstract][Full Text]
Stoppa-Lyonnet, D., Lauge, A., Sigaux, F., Stern;, M.-H., Vanasse, G. J., Concannon, P., Willerford, D. M.
(2000). No germline ATM mutation in a series of 16 T-cell prolymphocytic leukemias. Blood
96: 374-377
[Full Text]
Gatei, M., Scott, S. P., Filippovitch, I., Soronika, N., Lavin, M. F., Weber, B., Khanna, K. K.
(2000). Role for ATM in DNA Damage-induced Phosphorylation of BRCA1. Cancer Res.
60: 3299-3304
[Abstract][Full Text]
Khanna, K. K.
(2000). Cancer Risk and the ATM Gene: a Continuing Debate. JNCI J Natl Cancer Inst
92: 795-802
[Abstract][Full Text]
Wolden, S. L., Hancock, S. L., Carlson, R. W., Goffinet, D. R., Jeffrey, S. S., Hoppe, R. T.
(2000). Management of Breast Cancer After Hodgkin’s Disease. JCO
18: 765-765
[Abstract][Full Text]
Kim, S.-T., Lim, D.-S., Canman, C. E., Kastan, M. B.
(1999). Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members. J. Biol. Chem.
274: 37538-37543
[Abstract][Full Text]
Li, F. P., Whittemore, A. S.
(1999). Genetically Tailored Preventive Strategies: an Effective Plan for the Twenty-first Century?. Cancer Epidemiol. Biomarkers Prev.
8: 649-658
[Abstract][Full Text]
Beales, P L, Elcioglu, N, Woolf, A S, Parker, D, Flinter, F A
(1999). New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J. Med. Genet.
36: 437-446
[Abstract][Full Text]
Nichols, K. E., Levitz, S., Shannon, K. E., Wahrer, D. C.R., Bell, D. W., Chang, G., Hegde, S., Neuberg, D., Shafman, T., Tarbell, N. J., Mauch, P., Ishioka, C., Haber, D. A., Diller, L.
(1999). Heterozygous Germline ATM Mutations Do Not Contribute to Radiation-Associated Malignancies After Hodgkin's Disease. JCO
17: 1259-1259
[Abstract][Full Text]
Swift, M., Su, Y.
(1999). Link between breast cancer and ATM gene is strong. BMJ
318: 400-400
[Full Text]
Hacia, J. G., Sun, B., Hunt, N., Edgemon, K., Mosbrook, D., Robbins, C., Fodor, S. P.A., Tagle, D. A., Collins, F. S.
(1998). Strategies for Mutational Analysis of the Large Multiexon ATM Gene Using High-Density Oligonucleotide Arrays. Genome Res
8: 1245-1258
[Abstract][Full Text]
Chen, G., Lee, E. Y.-H. P.
(1996). The Product of the ATM Gene Is a 370-kDa Nuclear Phosphoprotein. J. Biol. Chem.
271: 33693-33697
[Abstract][Full Text]
Lieberman, H. B., Hopkins, K. M., Nass, M., Demetrick, D., Davey, S.
(1996). A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene. Proc. Natl. Acad. Sci. USA
93: 13890-13895
[Abstract][Full Text]
Elson, A., Wang, Y., Daugherty, C. J., Morton, C. C., Zhou, F., Campos-Torres, J., Leder, P.
(1996). Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl. Acad. Sci. USA
93: 13084-13089
[Abstract][Full Text]
Xu, Y, Baltimore, D
(1996). Dual roles of ATM in the cellular response to radiation and in cell growth control.. Genes Dev.
10: 2401-2410
[Abstract]
Langston, A. A., Malone, K. E., Thompson, J. D., Daling, J. R., Ostrander, E. A.
(1996). BRCA1 Mutations in a Population-Based Sample of Young Women with Breast Cancer. NEJM
334: 137-142
[Abstract][Full Text]
Savitsky, K, Bar-Shira, A, Gilad, S, Rotman, G, Ziv, Y, Vanagaite, L, Tagle, D., Smith, S, Uziel, T, Sfez, S, et, al.
(1995). A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science
268: 1749-1753
[Abstract]
Hartwell, L., Kastan, M.
(1994). Cell cycle control and cancer. Science
266: 1821-1828
[Abstract]
Evans, D G R, Fentiman, I S, McPherson, K, Asbury, D, Ponder, B A J, Howell, A
(1994). Fortnightly Review: Familial breast cancer. BMJ
308: 183-187
[Abstract][Full Text]
Meyn, M.
(1993). High spontaneous intrachromosomal recombination rates in ataxia-telangiectasia. Science
260: 1327-1330
[Abstract]
