A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression
Public Library of Science (PLoS)
MetadataShow full item record
Meyer, K., Maia, T., O'Reilly, M., Ghoussaini, M., Prathalingam, R., Porter-Gill, P., Ambs, S., et al. (2011). A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression. PLoS Genetics, 7 (7. e1002165)https://doi.org/10.1371/journal.pgen.1002165
Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream.
Alleles, Base Sequence, Binding Sites, Breast Neoplasms, Cell Line, Tumor, Chromosomes, Human, Pair 8, Colonic Neoplasms, Consensus Sequence, Female, Gene Expression Regulation, Neoplastic, Genetic Loci, Genetic Predisposition to Disease, Genotype, HCT116 Cells, Humans, Male, Models, Biological, Polymorphism, Single Nucleotide, Prostatic Neoplasms, RNA, Untranslated, Transcriptional Activation, YY1 Transcription Factor
This work was funded by Cancer Research UK (http://www.cancerresearchuk.org/) and by the Intramural Research Program, Division of Cancer Epidemiology and Genetics and Centre for Cancer Research, National Cancer Institute, National Institutes of Health, United States of America (http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
External DOI: https://doi.org/10.1371/journal.pgen.1002165
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263819