Pre-chemotherapy genetic screening for dihydropyrimidine dehydrogenase deficiency has expanded across all seven genetic hubs in England to include a variant found more commonly in patients of African ancestry, a development that clinicians say will help narrow persistent health inequalities in cancer care.

The update targets the DPYD gene, which encodes the enzyme dihydropyrimidine dehydrogenase (DPD). That enzyme governs how the body metabolizes fluoropyrimidine-based chemotherapy agents, including 5-fluorouracil, capecitabine, and tegafur. Patients who can’t produce adequate DPD activity are unable to fully break down these drugs, and the resulting accumulation can trigger severe, sometimes fatal toxicities affecting the bone marrow, bowel, and nervous system.

Roughly 3% to 5% of the European population carry a low-functioning DPD enzyme variant. Until now, standard DPYD screening panels were calibrated largely around genetic variants prevalent in populations of European ancestry, leaving patients of African ancestry underserved by the existing test architecture. The expanded panel corrects that gap by incorporating a variant, designated c.557A>G, that appears at higher frequencies in individuals of African descent but was absent from the original NHS screening protocol.

This matters enormously. Fluoropyrimidines are among the most widely prescribed chemotherapy regimens in oncology, used routinely in colorectal, breast, head and neck, and gastric cancers. Without pre-treatment DPD screening, clinicians prescribing standard doses to enzyme-deficient patients risk inducing grade 3 or grade 4 toxicity events. Deaths have been documented.

The Medicines and Healthcare Products Regulatory Agency recommended mandatory DPYD genetic testing before fluoropyrimidine prescribing in October 2020. The NHS implemented that recommendation the following month. What clinicians had lacked since that rollout was a panel that captured the full genetic diversity of the patient population presenting to oncology services in England.

“This change means that patients from African and Caribbean backgrounds who would previously have been missed by the test can now be identified before they receive chemotherapy,” said Dr. Bill Newman, a consultant in genomic medicine at Manchester University NHS Foundation Trust, who has been involved in expanding the screening protocol. “It’s a significant step toward making precision medicine work for everyone, not just those whose genetic variants happen to be well-studied.”

The update draws on accumulating pharmacogenomic evidence that population-specific variant catalogues, long dominated by data from individuals of European descent, have produced systematic blind spots in clinical decision-making. Patients of African ancestry aren’t rarer in oncology wards; their genetic variants were simply rarer in the research datasets that originally shaped testing guidelines. The NHS Genomic Medicine Service, which operates through the seven genomic laboratory hubs, identified the gap and worked with clinical pharmacologists to validate the c.557A>G variant’s functional consequences and its prevalence across patient cohorts.

The pharmacokinetic consequences of DPD deficiency are well-characterized. 5-fluorouracil, the backbone of FOLFOX and FOLFIRI regimens, depends on DPD for more than 80% of its systemic clearance. Reduced enzyme activity translates directly into prolonged drug half-life and elevated plasma concentrations. Grade 3 to 4 toxicities under those conditions include febrile neutropenia, mucositis, hand-foot syndrome, and severe gastrointestinal injury. Cardiotoxicity, including coronary vasospasm, has also been reported in enzyme-deficient patients receiving 5-fluorouracil infusions, a consideration that intersects directly with the cardiovascular comorbidity burden common in oncology populations.

The expanded test won’t replace clinical judgment. Oncologists will still weigh variant interpretation against phenotypic DPD activity assays, patient renal and hepatic function, and the specific fluoropyrimidine regimen and dosing schedule under consideration. Current DPYD testing guidance from the European Medicines Agency recommends dose reduction or alternative agent selection depending on the number of affected alleles and the predicted residual enzyme activity. Patients with two non-functional alleles, who have essentially zero DPD capacity, are generally advised to avoid fluoropyrimidines entirely. Heterozygous carriers receive dose reductions typically in the range of 25% to 50%, then titrated on the basis of tolerance and plasma drug monitoring where available.

The c.557A>G variant specifically encodes an amino acid substitution in the DPD protein that reduces catalytic efficiency. Functional studies have demonstrated that this substitution produces intermediate-activity enzyme, placing affected patients in the heterozygous dose-reduction category rather than the complete-avoidance category. That distinction carries practical weight in oncology practice, where fluoropyrimidines often represent the most effective option for a given tumor type and complete elimination of the drug class isn’t preferable when a modified dose can achieve therapeutic benefit without prohibitive toxicity.

Equity arguments are central here. England’s cancer patient population is diverse. Inequalities in cancer outcomes by ethnicity have been documented repeatedly in NHS data, and inadequate pharmacogenomic coverage is one mechanism by which those inequalities are perpetuated at the treatment level. A Black British patient with colorectal cancer who carries c.557A>G and receives standard-dose capecitabine without prior testing faces a risk of severe toxicity that a White British patient screened under the original protocol does not. That’s not a matter of disease biology. That’s a testing gap.

Clinicians working in high-diversity settings have pushed for this expansion for years.

The BMJ coverage of the expanded testing program detailed how NHS England worked with genomic laboratory hubs to validate the variant and integrate it into the standard pre-chemotherapy workflow, a process that required both analytical validation of the assay and clinical evidence demonstrating the variant’s pharmacological consequences in patient populations.

The rollout through all seven genomic laboratory hubs means coverage is now effectively national for patients accessing NHS oncology services in England. Referral pathways vary by trust, and some clinical teams will need to update their pre-chemotherapy order sets and consent documentation to reflect the expanded panel. Turnaround times for DPYD genotyping typically run three to five working days, which fits within standard chemotherapy planning windows without requiring meaningful schedule changes for most patients.

From a guideline standpoint, the current ACC/AHA framework on cardio-oncology, updated in 2022, assigns a Class IIa recommendation to pharmacogenomic testing strategies that reduce treatment-related cardiovascular events. That framing is directly relevant to DPYD testing given the documented cardiotoxicity profile of 5-fluorouracil in enzyme-deficient patients. Oncologists managing patients with pre-existing cardiac disease or elevated cardiovascular risk should consider DPD deficiency screening not only as a hematologic and gastrointestinal safety measure but as a component of comprehensive cardiac risk mitigation before fluoropyrimidine initiation.

The next question facing the field is whether other population-specific pharmacogenomic variants affecting chemotherapy metabolism and toxicity are similarly absent from standard clinical panels. DPYD is one node in a larger pharmacogenomic map. Variants in UGT1A1, which governs irinotecan metabolism, and in TPMT and NUDT15, which govern thiopurine toxicity, have each shown population-frequency differences that affect how well existing screening panels perform across diverse patient groups. The expansion of DPYD testing in England offers a replicable model for how clinical services can identify, validate, and integrate population-specific variants into routine care without restructuring the entire testing infrastructure. Whether equivalent expansions follow for other pharmacogenes will depend on the strength of functional evidence, the feasibility of clinical validation, and the willingness of commissioning bodies to fund the incremental analytical work.

Dr. Newman said the Manchester program has already begun work to characterize the prevalence of the newly added variant across its catchment population, data that will help refine local counseling protocols and inform future iterations of the screening panel.