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Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer

Meyer, KB; Maia, AT; O'Reilly, M; Teschendorff, AE; Chin, SF; Caldas, C; Ponder, BAJ; (2008) Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLOS BIOL , 6 (5) , Article e108. 10.1371/journal.pbio.0060108. Green open access

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Abstract

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 sites are occupied in vivo. In transient transfection experiments, the two SNPs can synergize giving rise to increased FGFR2 expression. We propose a model in which the Oct-1/Runx2 and C/EBPb binding sites in the disease-associated allele are able to lead to an increase in FGFR2 gene expression, thereby increasing the propensity for tumour formation.

Type: Article
Title: Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pbio.0060108
Publisher version: http://dx.doi.org/10.1371/journal.pbio.0060108
Language: English
Additional information: © 2008 Meyer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. We acknowledge the support of The University of Cambridge, Cancer Research UK, Hutchison Whampoa Limited and the NIHR Cambridge Biomedical Research Centre. BAJP is the Li Ka Shing Professor of Oncology at the University of Cambridge.
Keywords: FIBROBLAST-GROWTH-FACTOR, MMTV INSERTIONAL MUTAGENESIS, GENOME-WIDE ASSOCIATION, MALIGNANT HUMAN BREAST, NUCLEAR FACTOR, EXPRESSION, RECEPTOR, BINDING, RUNX2, CELLS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/121525
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