A novel polymorphism in the promoter region of ERBB4 is associated with breast and colorectal cancer risk.
OBJECTIVE
The receptor tyrosine kinase ERBB4/HER4 plays a role in cell division, migration, differentiation, as well as apoptosis, and is frequently overexpressed in breast and colorectal tumors. To understand the role of genetic variations in the regulation of ERBB4 expression, we identified new polymorphisms and investigated their functional implication and risk association with breast and colorectal cancer.


METHODS
We screened colorectal tumors from 92 patients for genetic variants at the ERBB4 ATG -1000 bp 5'-regulatory region by denaturing high-performance liquid chromatography and sequencing. Variants were subjected to DNA-protein interaction analyses (electrophoretic mobility shift assay), reporter gene assays in breast cancer cell lines MDA134 and MDA157, and immunohistochemical analyses of breast tumors. We established genotype frequencies within a breast cancer case-control collection (1,021 cases, 1,015 population-based controls) and a colorectal cancer case-control collection (459 cases, 569 blood donors) using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were assessed by multivariate logistic regression.


RESULTS
We identified five new germ line variants -815 A>T, -782 G>T, -638 insTC, -267 C>G, and -219 del10bp. Two variants showed in vitro functional effects. The -782T allele showed lower protein binding affinity and lower promoter activity compared with the -782G allele, however, the -815T allele showed higher protein binding affinity and higher promoter activity. The -782T variant was identified as a risk allele for breast and colorectal cancer (OR, 1.59; 95% CI, 1.06-2.34 and OR, 2.21; 95% CI, 1.22-3.99, respectively).


CONCLUSIONS
The ERBB4 -782 G>T polymorphism, by virtue of its in vitro functional implication and incidence, is a risk factor for breast and colorectal cancer.
Rokavec
Matjaz
M
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Justenhoven
Christina
C
Schroth
Werner
W
Istrate
Monica Adina
MA
Haas
Susanne
S
Fischer
Hans-Peter
HP
Vollmert
Caren
C
Illig
Thomas
T
Hamann
Ute
U
Ko
Yon-Dschun
YD
Glavac
Damjan
D
Brauch
Hiltrud
H
D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D066247:Receptor, ErbB-4; D012307:Risk Factors; D014162:Transfection
C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4