Noncoding cancer risk variants at 8q24: predicted regulatory effects on MYC

Abstract

Noncoding cancer-associated variants at the 8q24 locus may influence MYC, but the mechanisms through which these variants do this remain unclear. We hypothesized that selected 8q24 cancer-associated variants demonstrate evidence of regulatory activity near MYC and that risk alleles alter predicted chromatin accessibility. A panel of 12 variants from multiple GWAS of colon cancer, prostate cancer, and breast cancer was analyzed using ENCODE cCRE annotations, and then AlphaGenome was used to predict chromatin accessibility and contact maps, in silico mutagenesis, and gnomAD was used to plot ancestry differences. rs6983267 showed the strongest convergence of regulatory evidence, including being a proximal enhancer and meeting nomination requirements for AlphaGenome’s chromatin analysis. There was no clear relationship between increased regulatory effect and ancestry-frequency disparity due to the small variant panel. These findings suggest that rs6983267 shows strong predicted evidence to modulate the activity of a positive MYC enhancer. rs6983267 is supported as a plausible functional candidate, prioritizing it for future testing in prostate cell lines, although linkage disequilibrium prevents causal identification from GWAS alone. However, AlphaGenome’s results are predictions: the predictions generated in this study by AlphaGenome require experimental validation before they can be confirmed.