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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.

A Functional Variant at a Prostate Cancer Predisposition Locus at 8q24 Is Associated with PVT1 Expression