An allelic variant at the ATM locus is implicated in breast cancer susceptibility.

We have tested a simple procedure, disease association by locus stratification, for identifying breast cancer patients with pathogenetic allelic variants at several candidate loci. The strategy was based on the assumption of epistatic interactions of the candidates. We analyzed 66 independent cases from sib pairs affected with breast cancer that had previously been collected during an investigation of pathogenetic-allele-sharing at the HRAS1 mini-satellite locus. An exon 24 polymorphism of ATM, substituting arginine for proline was associated with breast cancer in these cases with an overall odds ratio of 4.5 (95% confidence interval, 1.2-20.5, nominal p = 0.02, 2-tail Fisher exact test). In the presence of a rare HRAS1 allele, the odds ratio increased to 6.9 (95% CI, 1.2-38.3, p = 0.03). Thus, our procedure identified at least one allelic variant of ATM associated with breast cancer, and indicated that the ATM locus may interact with HRAS1.

[1]  Y. Shiloh,et al.  Interaction between ATM protein and c-Abl in response to DNA damage , 1997, Nature.

[2]  G. Eichele,et al.  Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 , 1997, Nature.

[3]  Y. Shiloh,et al.  Fragments of ATM which have dominant-negative or complementing activity , 1997, Molecular and cellular biology.

[4]  K. Isselbacher,et al.  Heterozygous ATM mutations do not contribute to early onset of breast cancer , 1997, Nature Genetics.

[5]  Yonghong Xiao,et al.  Association of BRCA1 with Rad51 in Mitotic and Meiotic Cells , 1997, Cell.

[6]  M. Swift,et al.  Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. , 1996, Cancer genetics and cytogenetics.

[7]  C. Croce,et al.  ATM mutations in cancer families. , 1996, Cancer research.

[8]  M. James,et al.  The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation. , 1996, Cancer research.

[9]  M. Stratton,et al.  Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus , 1996, Nature Genetics.

[10]  S. Zienolddiny,et al.  A hereditary genetic marker closely associated with microsatellite instability in lung cancer. , 1995, Cancer research.

[11]  M. Lovett,et al.  A single ataxia telangiectasia gene with a product similar to PI-3 kinase. , 1995, Science.

[12]  N. Risch,et al.  An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. , 1993, The New England journal of medicine.

[13]  M. Swift,et al.  Breast and other cancers in families with ataxia-telangiectasia. , 1987, The New England journal of medicine.

[14]  G. Darlington,et al.  Isolation of DNA from biological specimens without extraction with phenol. , 1985, Clinical chemistry.

[15]  Ramon C. Littell,et al.  Asymptotic Optimality of Fisher's Method of Combining Independent Tests , 1971 .