Dpd Impairment Implication Of Dpyd Gene Polymorphism And Genetic Downregulation

Erratic DPD activity is a major cause of the marked pharmacokinetic variability of 5-FU. Drug-drug interactions (47,48), circadian patterns (12,49,50), and inter-gender (7,8) inter-ethnic differences (51,52,53,54,55) have been identified as putative causes for profound variations in DPD activities. Consequently, population studies of DPD activities displayed extremely wide ranges of values (17,56,57).

Genetic mutations are a major cause of DPD impairment (24,58). Polymorphism of the DPYD gene has been well characterized as an autosomal recessive disease, with 0.5% and 3%-5% of the Caucasian population being subsequently affected by total and partial deficiencies, respectively (7,59,60). Thymine uraciluria is a condition caused by inherited total DPD deficiency that can be either associated with neurological disorders or be asymptomatic (61,62,63).

The 150 kb DPYD gene is located on chromosome 1p22 and has 23 exons, ranging in size from 69 to 1404 pb, with 1 up to 20 kb introns (64, 65). The DPYD gene is highly polymorphic, and more than 40mutations have been described to date (24,66,67). The IVS14+1G>A splice-site mutation has been reported as the most common one (>50% of all mutations) in Western populations (23, 33,68). Several other SNPs and deletions have been documented with mixed, when not contradictory, effects reported

Table 1

Main Variant Alleles of the DPYD Gene. Reported Frequencies Are Collected from Caucasian Population Studies

Table 1

Main Variant Alleles of the DPYD Gene. Reported Frequencies Are Collected from Caucasian Population Studies

Polymorphism

Location

Effects of Genotype

DPD Expression

DPD Activity

Allele Frequency

Ref

IVS14+1 G>A

GT splice site

Exon 14 Skipping

Abolished/Decreased

Reduced/Unchanged

1

13, 68, 80

85 T>C

EXON2/21

cys29arg

Decreased

Reduced/Unchanged

<0,5

13, 80, 84

496 A>G

EXON6

met166val

Decreased

Reduced/Unchanged

<0,5

13

1627 A>G

EXON13

ile543 val

Decreased

Reduced

<0,5

13, 53

2194 G<A

EXON18

val732ile

Decreased

Reduced/Unchanged

<0,5

13, 53, 80

2846 A>T

EXON 22

asp949 val

Decreased

Reduced

<0,5

13, 76

delTCAT295-298

EXON4

DEL

Decreased

Reduced

<0,6

98

on enzymatic activity, protein expression, and, finally, clinical outcome upon 5-FU administration.

IVS14+1 G>A, 85 T>C, 496 A>G, 1627 A>G, 2194G>A, 2846 A>T and delTCAT295-298 are the most reported mutations affecting the DPYD gene, as summarized in Table 1. Other variations/deletions such as 611 C>T, 62 G>A, 257 C>T, 601 A>C, 632 A>G, 703 C>T, 1896 C>T, 1003 G>T, 2933 A>G, 1475 C>T, 1590T>C, 1601 G>A, 1679 T>G, delTG1039-1042, delC1897, and delT812 have been reported (51,69, 70, 71, 72, 73, 74, 75, 76). It has been suggested recently that besides DPYD sequence variations, promoter hypermethylation and other tissue-specific epigenetic regulations could have an impact on DPD activity as well (77,78, 79).

Consequently, predicting the actual impact of DPYD gene polymorphisms on DPD impairment and the subsequent clinical outcome with fluoropyrimidine drugs remains a difficult task. For instance, the IVS14+1 G>A mutation has been identified as being the most critical variation associated with life-threatening toxicities upon 5-FU administration (24). This polymorphism affects the splice recognition sequence of intron 14, thus leading to exon skipping and subsequent 165-bp deletion in the mRNA. However, further clinical studies failed to find a clear implication of this SNP in patients displaying severe/lethal toxicities after 5-FU or capecitabine intake, thus raising serious concern about the relevance of basing determination of DPD status in cancer patients on this sole mutation. For instance, retrospective screening for this polymorphism showed that only 2 out of 144 patients with severe toxicities upon 5-FU administration were bearing the IVS14+1 G>A mutation (35).

In another retrospective study, it was shown that none of the 6 patients with lethal toxicities after 5-FU or capecitabine administration displayed this polymorphism either, despite marked impairment in DPD activity (20,28,39). It is worth noting that significant differences in DPD activities have been demonstrated between liver and surrogate tissues (80), and single point mutations do not always impact systematically on DPD activity or expression. Such conflicting observations may be explained by the fact that in addition to genetic mutations, the importance of genetic and epigenetic regulations of the DPYD gene may be critical. Strong correlations have been found between DPD activity and mRNA levels, thus suggesting that transcriptional regulation should be an important mechanism leading to marked variations in DPD activity (81).

SP1 and, to a lesser extent, SP3 proteins have been identified as transcription activators of the DPYD gene, thus suggesting that assessment of the SP1/SP3 status might be used as a marker for DPD expression (82). Finally, it has been shown that methylation of the DPYD promoter region can be associated with impaired DPD activity (77), although conflicting data related to a possible tissue-specificity have been reported (79). Thus the exact mechanisms associating methylation with DPD down-regulation remain to be elucidated.

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