title: Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity.
abstract: According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C>T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A>C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.
authors.affiliation: Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany. s.tchatchou@dkfz.de
authors.forename: Sandrine
authors.initials: S
authors.lastname: Tchatchou
authors.forename: Angela
authors.initials: A
authors.lastname: Riedel
authors.forename: Stefan
authors.initials: S
authors.lastname: Lyer
authors.forename: Julia
authors.initials: J
authors.lastname: Schmutzhard
authors.forename: Olga
authors.initials: O
authors.lastname: Strobel-Freidekind
authors.forename: Sabine
authors.initials: S
authors.lastname: Gronert-Sum
authors.forename: Carola
authors.initials: C
authors.lastname: Mietag
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.forename: Bettina
authors.initials: B
authors.lastname: Schlehe
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Nina
authors.initials: N
authors.lastname: Ditsch
authors.forename: Anneke
authors.initials: A
authors.lastname: Blackburn
authors.forename: Linda Zhai
authors.initials: LZ
authors.lastname: Hill
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Jerry
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon-Mateeva
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins
chemical_list: D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins