title: ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy.
abstract: Biallelic inactivation of the ATM gene causes ataxia-telangiectasia (A-T), a complex neurological disease associated with a high risk of leukaemias and lymphomas. Mothers of A-T children, obligate ATM heterozygote mutation carriers, have a breast cancer (BC) relative risk of about 3. The frequency of ATM carriers in BC women with a BC family history has been estimated to be 2.70%. To further our clinical understanding of familial BC and examine whether haematological malignancies are predictive of ATM germline mutation, we estimated the frequency of heterozygote mutation carriers in a series of 122 BC women with a family history of both BC and haematological malignancy and without BRCA1/2 mutation. The gene screening was performed with a new high throughput method, EMMA (enhanced mismatch mutation analysis). Amongst 28 different ATM variants, eight mutations have been identified in eight patients: two mutations leading to a putative truncated protein and six being likely deleterious mutations. One of the truncating mutations was initially interpreted as a missense mutation, p.Asp2597Tyr, but is actually a splice mutation (c.7789G>T/p.Asp2597_Lys2643>LysfsX3). The estimated frequency of ATM heterozygote mutation carriers in our series is 6.56% (95% CI: 2.16-10.95), a significantly higher figure than that observed in the general population, estimated to be between 0.3 and 0.6%. Although a trend towards an increased frequency of ATM carriers was observed, it was not different from that observed in a population of familial BC women not selected for haematological malignancy as the frequency of ATM carriers was 2.70%, a value situated in the confidence interval of our study.
authors.affiliation: Service de Génétique, Institut Curie-Hôpital, 75248 Paris, France.
authors.forename: Laura La
authors.initials: LL
authors.lastname: Paglia
authors.forename: Anthony
authors.initials: A
authors.lastname: Laugé
authors.forename: Jérémie
authors.initials: J
authors.lastname: Weber
authors.forename: Jérôme
authors.initials: J
authors.lastname: Champ
authors.forename: Eve
authors.initials: E
authors.lastname: Cavaciuti
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Viovy
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases