
A common germline variant (rs4294451) located within a novel enhancer region for the anti-cancer drug metabolism gene DPYD controls its transcription and alters cellular sensitivity to the chemotherapeutic 5-fluorouracil.


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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, DPYD 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 vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD 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 DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.

### Competing Interest Statement

SMO reports former research support from Processa Pharmaceuticals, Inc., which are outside of the conduct of this study. SMO is an independent consultant for Processa Pharmaceuticals, Inc., in matters not related to this study. FI is currently an AbbVie employee and receives stocks from the company.

Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)

germline-variant-in-dpyd-enhancer-regulates-expression-and-alters-sensitivity-to-anti-cancer-drug-5-fluorouracil


Germline Variant in DPYD Enhancer Regulates Expression and Alters Sensitivity to Anti-Cancer Drug 5-Fluorouracil
