Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity.

TitleIdentification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity.
Publication TypeJournal Article
Year of Publication2010
AuthorsTchatchou S, Riedel A, Lyer S, Schmutzhard J, Strobel-Freidekind O, Gronert-Sum S, Mietag C, D'Amato M, Schlehe B, Hemminki K, Sutter C, Ditsch N, Blackburn A, Hill LZ, Jerry JD, Bugert P, Weber BHF, Niederacher D, Arnold N, Varon-Mateeva R, Wappenschmidt B, Schmutzler RK, Engel C, Meindl A, Bartram CR, Mollenhauer J, Burwinkel B
JournalHum Mutat
Volume31
Issue1
Pagination60-6
Date Published2010 Jan
ISSN1098-1004
KeywordsAdult, Aged, Breast Neoplasms, Breast Neoplasms, Male, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Receptors, Cell Surface, Risk Factors
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.

DOI10.1002/humu.21134
Alternate JournalHum. Mutat.
PubMed ID19830809