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EDITORIALS: Martin Lavin Role of the ataxia-telangiectasia gene (ATM) in breast cancer BMJ 1998; 317: 486-487 [Full text]

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Breast Cancer in A-T Heterozygotes

Michael Swift   (1 September 1998)

Breast Cancer in A-T Heterozygotes 1 September 1998
Michael Swift, Director and Professor Inst for the Genet Analysis of Common Dis, New York Med Coll Send response to journal: Re: Breast Cancer in A-T Heterozygotes	Breast Cancer in A-T Heterozygotes We welcome Lavin's recent editorial (1) that recognized the important role that the A-T gene plays in breast cancer, despite the attention given to two other genes, BRCA1/BRCA2, which are numerically less significant. It is important to emphasize that the evidence linking the A-T gene to breast cancer is more than "suggestive." In addition to the two separate smaller studies (2,3) referenced by Lavin, two large-scale epidemiological studies (4,5) have clearly indicated the increased risk of breast cancer among blood relatives of A-T patients. Using the precision of genotyping technology, and the statistically powerful unbiased index-test method for testing gene-disease associations (6), a 1996 study (7) provided the most compelling evidence that the A-T gene carriers have a 3.8-fold increased risk of breast cancer compared to non-carriers. With a p value of 0.0001, it is unlikely that this result arose by chance. Ever more precise estimates of the size of this risk will become available as more breast cancer cases in A-T families are genotyped. There is no conflict between these studies and the study by Fitzgerald et al. (8). The apparent lack of association found by Fitzgerald et al is likely due to selecting for their sample only breast cancer cases of onset before age 40, based on a speculation by Easton (9) that is not supported by any published data. Further, BRCA1/BRCA2 mutations accounted for a substantial proportion (13%) of Fitzgerald's study sample. An unmatched comparison group was used; it is highly unlikely that the distribution of the most important factors that affect gene frequency -- ethnicity and social class -- in their blood donor "control group" resembled that in the group of breast cancer patients. Such studies also have very low statistical power when the population frequency of heterozygotes is about 1-2%. Additionally, they sought A-T mutations through the protein truncation test, which typically fails to detect about half of all A-T mutations (10-12). In conclusion, the evidence supporting the association between mutations at the A-T locus and breast cancer is strong. No study with sound methodology has refuted this association. Michael Swift, Director and Professor Yun Su, Epidemiologist The Institute for the Genetic Analysis of Common Diseases New York Medical College 4 Skyline Drive Hawthorne, New York 10532 REFERENCES: 1. Lavin M. Role of the ataxia-telangiectasia gene (ATM) in breast cancer. BMJ 1998; 317: 486-487. 2. Pippard EC, Hall AJ, Barker DJ, Bridges BA. Cancer in homozygotes and heterozygotes of ataxia-telangiectasia and xeroderma pigmentosum in Britain. Cancer Res 1988; 48: 2929-2932. 3. Borresen AL, Anderson TI, Tretli S, Heiberg A, Moller P. Breast cancer and other cancers in Norweigian families with ataxia-telangiectasia. Genes Chromosomes Cancer 1990; 2: 339-340. 4. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in ataxia-telangiectasia families. N Engl J Med 1987; 316:1289-1294. 5. Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by ataxia-telangiectasia . N Engl J Med 1991; 325: 1831-1836. 6. Swift M, Kupper LL, Chase CL. Effective testing of gene-disease associations. Am J Hum Genet 1990; 47:266-274. 7. Athma P, Rappaport R, Swift, M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer, Cancer Genetics and Cytogenetics 1996; 92:130-134. 8. Fitzgerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet 1997; 15: 307-310. 9. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66: S177-182. 10. Savitsky K et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995; 268: 1749-1753. 11. Gilad S et al. Predominance of null mutations in ataxia-telangiectasia. Hum Mol Genet 1996; 5: 433-439. 12. Telatar M, Wang Z, Udar N et al. Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation screening. Am J Hum Genet 1996; 59: 40-44.