TY - JOUR
T1 - Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity
AU - Tchatchou, Sandrine
AU - Riedel, Angela
AU - Lyer, Stefan
AU - Schmutzhard, Julia
AU - Strobel-Freidekind, Olga
AU - Gronert-Sum, Sabine
AU - Mietag, Carola
AU - D'Amato, Mauro
AU - Schlehe, Bettina
AU - Hemminki, Kari
AU - Sutter, Christian
AU - Ditsch, Nina
AU - Blackburn, Anneke
AU - Hill, Linda Zhai
AU - Jerry, D. Joseph
AU - Bugert, Peter
AU - Weber, Bernhard H.F.
AU - Niederacher, Dieter
AU - Arnold, Norbert
AU - Varon-Mateeva, Raymonda
AU - Wappenschmidt, Barbara
AU - Schmutzler, Rita K.
AU - Engel, Christoph
AU - Meindl, Alfons
AU - Bartram, Claus R.
AU - Mollenhauer, Jan
AU - Burwinkel, Barbara
PY - 2010/1/1
Y1 - 2010/1/1
N2 - 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 riskincreasing 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 50′-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.
AB - 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 riskincreasing 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 50′-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.
KW - Breast cancer risk
KW - DMBT1 gene
KW - DMBT1 polymorphisms
KW - Risk factor
UR - http://www.scopus.com/inward/record.url?scp=74049142035&partnerID=8YFLogxK
U2 - 10.1002/humu.21134
DO - 10.1002/humu.21134
M3 - Article
C2 - 19830809
AN - SCOPUS:74049142035
SN - 1059-7794
VL - 31
SP - 60
EP - 66
JO - Human Mutation
JF - Human Mutation
IS - 1
ER -
