Abstract
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.
Highlights
Genome-wide association studies (GWAS) have identified multiple independent cancer susceptibility loci upstream of the MYC oncogene at chromosome 8q24: initial studies revealed one breast [2], three prostate [3], one bladder cancer [4] locus and one region conferring risk for multiple cancers including prostate, colon and ovarian cancer
We show that the risk locus is able to interact with two downstream genes, MYC and PVT1, and present evidence that PVT1 is a candidate new target gene regulated by the 8q24 risk region
The SDHS which maps to a repetitive element could not be detected by DNase-chip, as repetitive sequences are excluded from the array by design
Summary
Genome-wide association studies (GWAS) have identified multiple independent cancer susceptibility loci upstream of the MYC oncogene at chromosome 8q24 (reviewed in [1]): initial studies revealed one breast [2], three prostate [3], one bladder cancer [4] locus and one region conferring risk for multiple cancers including prostate, colon and ovarian cancer. The 8q24 region is currently considered the most important susceptibility region for prostate cancer, accounting for about 8% of the two-fold increase in risk observed in first degree relatives [3]. Breast tumours and metastatic prostate tumours carry frequent amplifications of the 8q24 region, spanning a large region covering both the MYC and the neighbouring PVT1 gene [9,10]. Both the MYC and the PVT1 genes are frequent targets for retroviral integration in mouse tumour assays [11]. The targets and function of PVT1 and its embedded miRNAs are still largely unknown
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