Nijmegen Breakage Syndrome mutations and risk of breast cancer.
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.
Bogdanova
Natalia
N
Gynecology Research Unit, Hannover Medical School, Hannover, Germany.
Feshchenko
Sergei
S
Schürmann
Peter
P
Waltes
Regina
R
Wieland
Britta
B
Hillemanns
Peter
P
Rogov
Yuri I
YI
Dammann
Olaf
O
Bremer
Michael
M
Karstens
Johann H
JH
Sohn
Christof
C
Varon
Raymonda
R
Dörk
Thilo
T
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
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins