allele-specific up-regulation of fgfr2 increases susceptibility to breast cancerallele-specific老年病的fgfr2会增加患乳腺癌的几率.pdfVIP

PLoS BIOLOGY Allele-Specific Up-Regulation of FGFR2 Increases Susceptibility to Breast Cancer 1*[ 1,2[ 1 1,2 1,2 Kerstin B. Meyer , Ana-Teresa Maia , Martin O’Reilly , Andrew E. Teschendorff , Suet-Feung Chin , Carlos Caldas1,2, Bruce A. J. Ponder1,2 1 Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom, 2 Department of Oncology, University of Cambridge, Cambridge, United Kingdom The recent whole-genome scan for breast cancer has revealed the FGFR2 (fibroblast growth factor receptor 2) gene as a locus associated with a small, but highly significant, increase in the risk of developing breast cancer. Using fine-scale genetic mapping of the region, it has been possible to narrow the causative locus to a haplotype of eight strongly linked single nucleotide polymorphisms (SNPs) spanning a region of 7.5 kilobases (kb) in the second intron of the FGFR2 gene. Here we describe a functional analysis to define the causative SNP, and we propose a model for a disease mechanism. Using gene expression microarray data, we observed a trend of increased FGFR2 expression in the rare homozygotes. This trend was confirmed using real-time (RT) PCR, with the difference between the rare and the common homozygotes yielding a Wilcox p-value of 0.028. To elucidate which SNPs might be responsible for this difference, we examined protein–DNA interactions for the eight most strongly disease-associated SNPs in different breast cell lines. We identify two cis-regulatory SNPs that alter binding affinity for transcription factors Oct-1/Runx2 and C/EBPb, and we demonstrate that both si