title: Nijmegen Breakage Syndrome mutations and risk of breast cancer.
abstract: Mutations in the NBS1 gene have been identified as disease-causing mutations in patients with Nijmegen Breakage Syndrome (NBS), but their clinical impact on breast cancer susceptibility has remained uncertain. We determined the frequency of 2 NBS mutations, 657del5 and R215W, in two large series of breast cancer cases and controls from Northern Germany and from the Republic of Belarus. The 5-bp-deletion 657del5 was identified in 15/1,588 cases (0.9%) from Belarus and in 1/1,076 cases (0.1%) from Germany but in only 1/1,014 population controls from Belarus and 0/1017 German controls (p < 0.01). The missense substitution R215W was observed in 9/1,588 Byelorussian and 9/1,076 German patients (0.6% and 0.8%, respectively) but was also present in 5/1,014 Byelorussian and 2/1,017 German control individuals (adjusted OR = 1.9, 95%CI 0.8-4.6, p = 0.18). Studies of lymphoblastoid cell lines revealed that NBS1/p95 protein levels were reduced to 70% in cells from a heterozygous breast cancer patient carrying R215W and to 15% in cells from a NBS patient compound heterozygous for 657del5/R215W suggesting that the R215W substitution may be associated with protein instability. Levels of radiation-induced phosphorylation of Nbs1/p95(Ser343) were reduced to 60% and 35% of wildtype, respectively. Neither age at diagnosis nor family history of breast cancer differed significantly between carriers and noncarriers of NBS mutations. The combined data are in line with an about 3-fold increase in breast cancer risk for female NBS heterozygotes (OR 3.1; 95%CI 1.4-6.6) and indicate that the 657del5 deletion and perhaps the R215W substitution contribute to inherited breast cancer susceptibility in Central and Eastern Europe.
authors.affiliation: Gynecology Research Unit, Hannover Medical School, Hannover, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Sergei
authors.initials: S
authors.lastname: Feshchenko
authors.forename: Peter
authors.initials: P
authors.lastname: Schürmann
authors.forename: Regina
authors.initials: R
authors.lastname: Waltes
authors.forename: Britta
authors.initials: B
authors.lastname: Wieland
authors.forename: Peter
authors.initials: P
authors.lastname: Hillemanns
authors.forename: Yuri I
authors.initials: YI
authors.lastname: Rogov
authors.forename: Olaf
authors.initials: O
authors.lastname: Dammann
authors.forename: Michael
authors.initials: M
authors.lastname: Bremer
authors.forename: Johann H
authors.initials: JH
authors.lastname: Karstens
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D049932:Nijmegen Breakage Syndrome / Q000453:epidemiology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins