Genetic polymorphism in the
DPYD gene is the most well-recognized cause of DPD deficiency, with the clinically most relevant polymorphism being
DPYD*2A. The frequency of
DPYD*2A is 1% to 2% in the Western world [
13], and by screening for
DPYD*2A, only 25% of DPD-deficient patients are identified [
2]. The prevalence of the
DPYD*2A polymorphism is 0.6% in the Turkish population [
14], but no other studies regarding the frequency of the
DPYD*2A polymorphism or other variants have been reported in the Middle Eastern or Lebanese population. When we wanted to test the patient for DPYD deficiency, two options were available: either screen for the most common variants or sequence the coding region or highly conserved exon-intron splice junctions. One meta-analysis recommended testing for the
DPYD variants IVS14+1G>A and 2846A>T [
15], and another meta-analysis recommended testing the variants c.1679 T>G and c.1236G>A/HapB3 in addition to the two previously established variants [
16]. We elected to perform coding region and highly conserved exon-intron splice junction sequencing because we had no previous data reported from Lebanon, knowing that such a technique may lead to findings that are to be additionally explained, confirmed, and validated against a control population, which will open the door for further research studies. Our patient was found to have not only the
DPYD*2A polymorphism but also two other deficiency-associated variants that would have been missed if the entire coding region had not been sequenced. As far as we are aware, this is the first report of three pathogenic or deficiency-associated variants in the
DPYD gene in the same patient. One study from the United Kingdom recently identified the c.1601G>A variant to be significantly associated with fluoropyrimidine toxicity [
3]. In this study, two patients were compound heterozygous for the variants c.1601G>A/c.1905+1G>A and c.1601G>A/c.2846A>T. Both experienced grade 4 toxicity requiring hospital admission for 16 and 19 days, respectively. The
DPYD*2A variant may be sufficient to cause the toxicity seen, but we cannot be sure; perhaps the presence of the two other variants added to the severity of the toxicity. In addition, two of the three variants must occur on the same allele, and perhaps having two variants on the same allele contributed to a significant decrease in DPD activity. The patient received two other chemotherapeutic agents that might be partially responsible for the adverse events experienced. However, oxaliplatin toxicity generally manifests as neurological abnormalities along with liver toxicity [
17]. As for irinotecan, toxicity presents mostly as severe diarrhea and myelosuppression, both of which our patient experienced [
18]. The fact that the patient also has Gilbert’s syndrome may have caused irinotecan toxicity that compounded the symptoms caused by DPD deficiency. Although irinotecan has side effects similar to 5-FU, many of the side effects our patient experienced are a rare occurrence in irinotecan toxicity but are very common in 5-FU toxicity.
Had the variant DPYD*2A been tested alone and had it not been present, the toxicity would have been blamed on irinotecan alone, and 5-FU would have been used without reductions, which could have harmed the patient.