Page 66 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Table 1. Known DPYD variants stratified by level of evidence on the association with toxicity and predicted DPD enzyme activity
The variants in this table were selected based on literature in Supplementary Table 1 and 2. However, high allele frequency variants reported only in case reports with fluoropyrimidine toxicity were excluded. For these variants the association with DPD enzyme activity, and resulting severe fluoropyrimidine-induced toxicity, cannot be determined.
Level of evidence DPD enzyme activity
Fully functionalc Reduced functionalityd
Sufficient evidencea
DPYD *4 = c.1601G>A DPYD *5 = c.1627A>G DPYD *9A = c.85T>C
c.2846A>T c.[1236G>A;1129- 5923C>G] (hapB3)e
Insufficient evidenceb
c.496A>G
c.1129-15T>C (IVS10-15T>C) DPYD*6 = c.2194G>A
c.1896T>C
DPYD*3 = c.1897delC
DPYD*7 = c.299_302del
DPYD*8 = c.703C>T
DPYD *9B = c.85T>C(;)c.2657G>A DPYD *10 = c.2983G>T
DPYD *11 = c.1003G>T
DPYD *12 = c.62G>A
c.1156G>T
c.1651G>A
c.1845G>T
c.300C>Ag
c.1024G>Ag
c.1025A>Gg
c.1475C>Tg
c.1774C>Tg c.(2058_2059)_(2299_2300)dup
Fully dysfunctionalf
DPYD*2A = c.1905+1G>A (IVS14+1G>A)
DPYD*13 = c.1679T>G
a DPWG has concluded an association between fully functional variants and no resulting toxicity, and an association between reduced functionality variants or fully dysfunctional variants and association with the onset of severe fluoropyrimidine-induced toxicity;
b DPWG has concluded there is insufficient evidence to associate a predicted DPD enzyme activity for these variants and the onset of severe fluoropyrimidine-induced toxicity;
c These variants are not included in the prospective DPYD genotyping panel, as there is no effect on predicted DPD enzyme activity, and therefore there is no association with the onset of severe fluoropyrimidine-induced toxicity;
d The effect of the variant on the protein sequence suggests that the protein may still be partially functional. Therefore residual metabolic DPD capacity may be present;
e Variant c.1236G>A, which does not lead to an alternative amino acid, is in complete linkage disequilibrium with variant c.1129-5923C>G, which leads to aberrant splicing in mRNA, which leads to a premature stop codon as a result. The resulting DPD enzyme activity is 50% of the normal activity.
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