Mutation analysis of the ERCC4/FANCQ gene in hereditary breast cancer.
The ERCC4 protein forms a structure-specific endonuclease involved in the DNA damage response. Different cancer syndromes such as a subtype of Xeroderma pigmentosum, XPF, and recently a subtype of Fanconi Anemia, FA-Q, have been attributed to biallelic ERCC4 gene mutations. To investigate whether monoallelic ERCC4 gene defects play some role in the inherited component of breast cancer susceptibility, we sequenced the whole ERCC4 coding region and flanking untranslated portions in a series of 101 Byelorussian and German breast cancer patients selected for familial disease (set 1, n = 63) or for the presence of the rs1800067 risk haplotype (set 2, n = 38). This study confirmed six known and one novel exonic variants, including four missense substitutions but no truncating mutation. Missense substitution p.R415Q (rs1800067), a previously postulated breast cancer susceptibility allele, was subsequently screened for in a total of 3,698 breast cancer cases and 2,868 controls from Germany, Belarus or Russia. The Gln415 allele appeared protective against breast cancer in the German series, with the strongest effect for ductal histology (OR 0.67; 95%CI 0.49; 0.92; p = 0.003), but this association was not confirmed in the other two series, with the combined analysis yielding an overall Mantel-Haenszel OR of 0.94 (95% CI 0.81; 1.08). There was no significant effect of p.R415Q on breast cancer survival in the German patient series. The other three detected ERCC4 missense mutations included two known rare variants as well as a novel substitution, p.E17V, that we identified on a p.R415Q haplotype background. The p.E17V mutation is predicted to be probably damaging but was present in just one heterozygous patient. We conclude that the contribution of ERCC4/FANCQ coding mutations to hereditary breast cancer in Central and Eastern Europe is likely to be small.
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
Sandra
S
Kohlhase
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany ; Clinics of Radiation Oncology, Hannover Medical School, Hannover, Germany.
Natalia V
NV
Bogdanova
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
Peter
P
Schürmann
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany ; Institute of Biochemistry and Genetics, Ufa, Russia.
Marina
M
Bermisheva
Institute of Biochemistry and Genetics, Ufa, Russia.
Elza
E
Khusnutdinova
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
Natalia
N
Antonenkova
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
Tjoung-Won
TW
Park-Simon
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
Peter
P
Hillemanns
Clinics of Radiation Oncology, Hannover Medical School, Hannover, Germany.
Andreas
A
Meyer
Clinics of Radiation Oncology, Hannover Medical School, Hannover, Germany.
Hans
H
Christiansen
Institute of Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany.
Detlev
D
Schindler
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
Thilo
T
Dörk
D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000151:congenital* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005061:Europe, Eastern; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D012306:Risk; D016019:Survival Analysis
D004268:DNA-Binding Proteins; C095888:xeroderma pigmentosum group F protein