Germline <i>cis</i> variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (<i>DPYD</i>).

Abstract

Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, <i>DPYD</i> gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and <i>vivo</i> that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls <i>DPYD</i> transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and <i>DPYD</i> promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.