Dihydropyrimidine dehydrogenase deficiency

Presentation

Genetics

DPD deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Diagnosis

Detection

A small number of genetic variants have been repeatedly associated with DPD deficiency, such as IVS14+1GA mutation in intron 14 coupled with exon 14 deletion (a.k.a. DPYD2A), 496AG in exon 6; 2846AT in exon 22 and T1679G (a.k.a. DPYD13) in exon 13. Testing patients for these allelic variants usually show high specificity (i.e., bearing the mutation means that severe toxicity will occur indeed) but very low sensitivity (i.e., not bearing the mutation does not mean that there is no risk for severe toxicities). Alternatively, phenotyping DPD using ex-vivo enzymatic assay or surrogate testing (i.e., monitoring physiological dihydrouracil to uracil ratio in plasma) has been presented as a possible upfront strategy to detect DPD deficiency. 5-FU test dose (i.e., preliminary administration of a small dose of 5-FU with pharmacokinetics evaluation) has been proposed as another possible alternative strategy to secure the use of fluoropyrimidine drugs.. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has issued guidelines supporting 50% dose reduction in heterozygous carriers of the decreased function variants rs3918290 (c.1905+1GA), rs55886062 (c.1679TG), rs56038477(c.1236GA), rs67376798 (c.2846AT), c.2846AT (rs67376798) or c.1129–5923CG (rs75017182; HapB3 or its tagging SNP c.1236GA; rs56038477)

Although DPYD pre-treatment screening has been proven to improve drug safety for DPYD2A carriers by the Food and Drug Administration, the current (version 2016) European Society for Medical Oncology (ESMO) guidelines do not “routinely recommend” upfront genotyping of DPYD2A before the administration of 5‐FU in metastatic CRC (mCRC) patients. While oncology societies in the United States do not recommend systematic testing. Instead, on April 30, 2020, the European Society for Medical Oncology issued a document recommending genetic testing. France is the first and only country to require pre-dose DPD testing before administering 5-FU or capecitabine in 2018.

References

References

1. (Jan 1988). "Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity". J Clin Invest.
2. Van Kuilenburg AB. (Mar 2006). "Screening for dihydropyrimidine dehydrogenase deficiency: to do or not to do, that's the question". Cancer Investigation.
3. (Aug 2004). "Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy". Clinical Advances in Hematology & Oncology.
4. (Nov 2006). "Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy". Clinical Colorectal Cancer.
5. (Dec 2007). "Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit?". Trends in Pharmacological Sciences.
6. "CPIC® Guideline for Fluoropyrimidines and DPYD – CPIC".
7. Yau, Tung On. (October 2019). "Precision treatment in colorectal cancer: Now and the future". JGH Open.
8. (2020). "All You Need to Know About DPYD Genetic Testing for Patients Treated With Fluorouracil and Capecitabine: A Practitioner-Friendly Guide". JCO Oncology Practice.
9. (2020). "Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France". European Journal of Cancer.