Pharmacogenomic DPYD Variant and 5-Fluorouracil Dosing
A 65-year-old man with stage III colon cancer is scheduled to receive adjuvant FOLFOX (5-fluorouracil, leucovorin, oxaliplatin). Before starting, the oncology team orders a pharmacogenomic panel that includes DPYD genotyping. The panel reports the patient is heterozygous for DPYD c.1905+1G>A (DPYD*2A), a splice-site variant associated with reduced dihydropyrimidine dehydrogenase activity. The patient has no prior history of 5-FU toxicity. The oncology team is unfamiliar with DPYD testing and asks the molecular genetic pathology fellow for guidance. The laboratory uses a targeted genotyping assay that covers four DPYD variants: *2A, *13, c.2846A>T, and HapB3. The report states that the patient is a *2A heterozygote and provides a recommendation to reduce the starting dose of 5-FU by 50%.
1. What is the clinical significance of the DPYD*2A variant, and how should the 5-FU dose be adjusted?
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DPYD*2A (c.1905+1G>A) is a non-functional variant that causes reduced DPYD enzyme activity, leading to decreased catabolism of 5-fluorouracil (5-FU) and increased risk of severe or fatal toxicity. Heterozygotes have intermediate DPYD activity (approximately 50% of normal) and are at increased risk for grade 3-4 toxicity. Clinical guidelines (e.g., CPIC) recommend reducing the starting dose of 5-FU by 50% in patients who are heterozygous for a no-function DPYD variant, such as *2A, and then titrating based on toxicity and therapeutic drug monitoring. For homozygous or compound heterozygous patients, alternative chemotherapy is recommended. The dose reduction should be clearly communicated to the oncology team, and the patient should be monitored closely for toxicity.
2. What are the limitations of the targeted DPYD genotyping assay, and what additional testing might be considered?
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The targeted assay only detects four common DPYD variants, which account for a subset of reduced-function alleles. Rare or novel variants in DPYD would not be detected. Additionally, the assay may not detect large deletions or duplications. If the patient has a phenotype suggestive of DPYD deficiency (e.g., prior 5-FU toxicity) but the targeted test is negative, additional testing such as full-gene sequencing or deletion/duplication analysis could be considered. However, in this case, the patient is heterozygous for *2A, so the result is actionable. The report should note the limitations of the assay, including that it does not detect all possible DPYD variants. The laboratory should also ensure that the variant nomenclature is correct and that the interpretation follows CPIC guidelines.