title: Association of common ATM polymorphism with bilateral breast cancer.
abstract: The ATM kinase has an essential role in maintaining genomic integrity. Loss of both ATM alleles results in ataxia-telangiectasia (A-T), a rare autosomal recessive neuroimmunologic disorder associated with cancer susceptibility. Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for malignancy, in particular, female breast cancer. In the current study, a full mutation analysis of the ATM gene was carried out in patients from 121 breast or breast-ovarian cancer families. We discovered that the combination of 5557G-->A in cis position with IVS38-8 T-->C was associated with bilateral breast cancer (OR = 10.2; 95% CI = 3.1-33.8; p = 0.001). As the 5557G-->A change has been reported to affect an exonic splicing enhancer, we hypothesized that the observed composite allele could have some effect on the correct splicing of exon 39. However, no aberrant transcripts were detected, but ATM expression levels of lymphoblast cell lines from heterozygous carriers of this combination allele were lower than from noncarriers (p = 0.09). Lowered gene expression levels may have direct influence on the activities in DNA damage recognition and response pathways, as well as other genome integrity maintenance functions. Based on the results, we propose a cancer risk-modifying effect for the ATM 5557G-->A, IVS38-8T-->C composite allele.
authors.affiliation: Department of Clinical Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Heikkinen
authors.forename: Katrin
authors.initials: K
authors.lastname: Rapakko
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Karppinen
authors.forename: Hannele
authors.initials: H
authors.lastname: Erkko
authors.forename: Pentti
authors.initials: P
authors.lastname: Nieminen
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; 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