Summary

DPYD rs3918290 determines whether your body can safely metabolise fluoropyrimidine chemotherapy drugs (5-FU, capecitabine) — carriers of the T allele have severely impaired drug clearance, and standard doses in TT carriers can be fatal, making this the highest-consequence pharmacogenomic finding in the entire KB and the reason EMA now mandates DPYD testing before fluoropyrimidine treatment in Europe.

Genotype spectrum

CC (wild-type)

Full DPD enzyme function. If you ever need fluoropyrimidine chemotherapy, standard dosing protocols apply.

CT (heterozygous, carrier)

Knowing this BEFORE chemotherapy starts is genuinely life-protecting. A 50% dose reduction in CT carriers dramatically reduces severe toxicity while maintaining treatment efficacy.

TT (homozygous deficient)

This knowledge is potentially life-saving. Without pre-treatment testing, TT carriers receiving standard 5-FU doses face a medical emergency.

Practical takeaway

For CC Carriers (Normal DPD)
• Standard fluoropyrimidine dosing if chemotherapy is indicated.
• Standard oncology monitoring during treatment.
• No specific pharmacogenomic action needed.
For CT Carriers (Intermediate DPD — ~1-2% of Europeans)
• 50% initial dose reduction for 5-FU, capecitabine, or tegafur. CPIC and EMA recommendation.
• Dose escalation may be considered after first cycle if tolerability permits, under close monitoring.
• Inform every oncologist who may prescribe chemotherapy. Add to permanent medical records.
• Carry documentation of DPYD status — emergencies may arise where chemotherapy is initiated rapidly.
For TT Carriers (DPD Deficient — very rare)
• Fluoropyrimidines are contraindicated. Full stop.
• Alternative regimens exist for every major cancer indication.
• This must be in your medical records permanently.
• Inform family members — first-degree relatives have a 50% chance of being carriers.

Expected response window: Fluoropyrimidine toxicity in DPD-deficient patients typically manifests within the first treatment cycle (days 3-14 after first dose). Severity is dose-dependent and can escalate rapidly.

Evidence detail

What This Gene Does

DPYD encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for breaking down over 80% of administered 5-fluorouracil (5-FU). 5-FU and its oral prodrug capecitabine are among the most widely used chemotherapy agents worldwide — standard treatment for colorectal, breast, head/neck, gastric, and pancreatic cancers. DPD converts 5-FU to inactive dihydrofluorouracil in the liver. If DPD activity is reduced or absent, 5-FU accumulates to toxic levels, causing severe and potentially lethal toxicity.

The rs3918290 variant (IVS14+1G>A, also called DPYD*2A) is a splice-site mutation that causes exon 14 skipping, producing a non-functional enzyme. This is the most clinically significant DPYD variant with the highest predictive value for severe fluoropyrimidine toxicity.

Mechanism

DPD is expressed primarily in the liver and is responsible for the first catabolic step of pyrimidine degradation:

5-FU → [DPD/DPYD] → Dihydrofluorouracil (DHFU) → further catabolism → excretion
↑
rs3918290 T allele
destroys this step

DPD catabolises >80% of administered 5-FU within minutes. The remaining ~20% is anabolised to cytotoxic metabolites (FdUMP, FUTP, FdUTP) that kill cancer cells by inhibiting thymidylate synthase and incorporating into RNA/DNA.

When DPD is absent or severely reduced, the catabolic pathway is blocked. The proportion of 5-FU shunted to the anabolic (cytotoxic) pathway increases dramatically. The result is massive overexposure to cytotoxic metabolites — affecting all rapidly dividing cells: bone marrow (pancytopenia), GI mucosa (severe mucositis, diarrhoea), skin (hand-foot syndrome), and immune system (neutropenic sepsis).

The rs3918290 splice-site mutation (G>A at the intron 14 donor site) causes complete skipping of exon 14, producing a truncated, non-functional protein. In heterozygotes, one functional allele produces approximately 30-70% of normal DPD activity — enough for endogenous pyrimidine metabolism but insufficient for safe clearance of pharmacological 5-FU doses.

DPYD

Summary

Genotype spectrum

Practical takeaway

Evidence detail

Sources (5)