title: A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer.
abstract: Blood relatives of patients with ataxia-telangiectasia (A-T) have an increased risk to develop breast cancer. Allelic heterogeneity has made it difficult to confirm the role of ATM, the gene mutated in A-T, for breast cancer susceptibility in the general population. We now report that a nonsense mutation, p.E1978X (c.5932G>T), is both a classical A-T mutation and a breast cancer susceptibility allele in Eastern European populations. In a case-control study from Belarus, the E1978X mutation was identified in 10/1,891 Byelorussian breast cancer cases (0.5%) compared with 1/1,019 population controls [odds ratio (OR): 5.4; 95% confidence interval (95% CI), 0.7-42.4, P = 0.1]. A second case-control study from Russia identified the E1978X mutation in two Russian and one Ukrainian cases out of 611 breast cancer patients but not in any Russian or Ukrainian controls (P = 0.1). In a third case-control study from Poland, E1978X was observed in 7/3,910 Polish breast cancer cases (0.2%) compared with 1/2,010 cancer-free population controls (OR: 3.6; 95% CI: 0.4-29.3, P = 0.4). In the combined analysis, E1978X was significantly associated with breast cancer (Mantel-Haenszel OR: 5.6, 95% CI: 1.3-21.4, P = 0.01). Taken together, this study provides first evidence for the association of a common A-T causing mutation with breast cancer in Eastern European founder populations.
authors.affiliation: Department of Obstetrics and Gynaecology, Hannover Medical School, Carl-Neuberg-St. 1, 30625, Hannover, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Cezary
authors.initials: C
authors.lastname: Cybulski
authors.forename: Marina
authors.initials: M
authors.lastname: Bermisheva
authors.forename: Ihor
authors.initials: I
authors.lastname: Datsyuk
authors.forename: Paria
authors.initials: P
authors.lastname: Yamini
authors.forename: Peter
authors.initials: P
authors.lastname: Hillemanns
authors.forename: Natalja Nikolaevna
authors.initials: NN
authors.lastname: Antonenkova
authors.forename: Elza
authors.initials: E
authors.lastname: Khusnutdinova
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D018275:Carcinoma, Lobular / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005192:Family Health; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D017354:Point Mutation; D011044:Poland / Q000453:epidemiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D002094:Republic of Belarus / Q000453:epidemiology; D012426:Russia / Q000453:epidemiology; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology; D014455:Ukraine / Q000453:epidemiology / Q000208:ethnology
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases