title: Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer.
abstract: Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G>A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on familial breast cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German familial breast cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with familial breast cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk familial breast cancer (OR = 1.32, 95% CI 1.06-1.65). The analysis of p53 MspI 1798G>A, which is completely linked to p53PIN3, showed a significantly increased familial breast cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.12-4.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased breast cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for familial breast cancer susceptibility.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. wirtenberger@dkfz.de
authors.forename: Michael
authors.initials: M
authors.lastname: Wirtenberger
authors.forename: Bernd
authors.initials: B
authors.lastname: Frank
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klaes
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D001816:Bloom Syndrome; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D005090:Exodeoxyribonucleases; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D053484:RecQ Helicases; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014898:Werner Syndrome; D000071657:Werner Syndrome Helicase
chemical_list: D016159:Tumor Suppressor Protein p53; D005090:Exodeoxyribonucleases; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase