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Known variant DPYD alleles do not explain DPD deficiency in cancer patients
E S Collie-Duguid1, M C Etienne, G Milano
1University of Aberdeen, Department of Medicine and Therapeutics, Institute of Medical Sciences, Foresterhill, UK. e.collie-duguid@abdn.ac.uk
Abstract:
Dihydropyrimidine dehydrogenase (DPD) degrades over 80% of administered 5-fluorouracil (5FU), thereby regulating the efficacy of this commonly used anticancer agent. DPD activity is highly variable (8-21-fold) and individuals with reduced activity have a high risk of 5FU toxicity. DPYD encodes DPD protein and 13 different mutations have been reported in DPD-deficient subjects. However, the contribution of these variant genotypes to polymorphic DPD activity in vivo is not clear. The previously described DPYD mutations are contained in 10 exons. These 10 exons were sequenced in a cohort of cancer patients with reduced (n = 23) or normal (n = 14) DPD activity to determine the contribution of each variant allele to low DPD activity in vivo. Eight of the 13 previously defined DPYD mutations (G62A, delta TCAT295-298, C703T, G1003T, G1156T, delta C1897, G2657A, and G2983T) were not detected. A previously defined exon 13 mutation (G1601A) was detected in three individuals with reduced DPD activity. An exon 14 splice donor site mutation (intron14 G1A) was detected in a normal DPD activity individual. It was demonstrated that T85C, A1627G and G2194A are common polymorphisms. A novel exonic mutation (T1679G) was detected in a patient with reduced DPD activity and 5FU toxicity. In addition, three novel common polymorphisms were detected in introns 10 and 13. Only three patients did not have any mutations and 30 had multiple DPYD mutations in the regions examined. However, only 17% (4/23) of the patients with a low DPD phenotype have a molecular basis for reduced activity. Although novel DPYD variants have been identified in this study, the 17 DPYD mutations now described do not entirely explain polymorphic DPD activity and toxic response to 5FU. These data emphasize the complex nature of the molecular mechanisms controlling polymorphic DPD activity in vivo.
Insights
Dihydropyrimidine dehydrogenase (DPD) activity variability impacts 5-fluorouracil (5FU) cancer treatment efficacy and toxicity. This study found that known and novel DPYD gene variants do not fully explain reduced DPD activity in patients.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Oncology
Background:
- Dihydropyrimidine dehydrogenase (DPD) is crucial for metabolizing 5-fluorouracil (5FU), a widely used anticancer drug.
- DPD activity exhibits significant inter-individual variability, leading to a high risk of 5FU toxicity in patients with reduced enzyme activity.
- The DPYD gene encodes DPD, and while several mutations are linked to DPD deficiency, their contribution to variable activity in vivo remains unclear.
Purpose of the Study:
- To investigate the contribution of known and novel DPYD gene variants to polymorphic DPD activity in cancer patients.
- To determine the molecular basis for reduced DPD activity and its association with 5FU toxicity.
Main Methods:
- Sequencing of 10 key exons of the DPYD gene in cancer patients with reduced (n=23) or normal (n=14) DPD activity.
- Analysis of previously defined and novel DPYD mutations and polymorphisms.
- Correlation of identified DPYD variants with DPD activity phenotypes and 5FU toxicity.
Main Results:
- Eight previously defined DPYD mutations were not detected in the study cohort.
- A known exon 13 mutation (G1601A) and a novel exonic mutation (T1679G) were found in patients with reduced DPD activity.
- Common polymorphisms (T85C, A1627G, G2194A) and novel intronic polymorphisms were identified.
- Only 17% of patients with reduced DPD activity had a clear molecular basis for their low enzyme levels.
- Multiple DPYD mutations were found in most patients, but did not fully explain the observed DPD activity variations.
Conclusions:
- The identified DPYD mutations and polymorphisms do not entirely account for the polymorphic DPD activity observed in vivo.
- The molecular mechanisms underlying variable DPD activity and 5FU response are complex and not fully elucidated.
- Further research is needed to identify additional genetic factors contributing to DPD activity and 5FU pharmacogenomics.