Page 67 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

DPWG guideline for DPYD and fluoropyrimidines
Both variants are part of haplotype B3;
f The effect of the variant on the protein sequence suggests that the protein may be fully dysfunctional;
g These variants have decreased in vitro enzyme activity.
Variants from the table according to multiple nomenclatures (HGVS: NM_000110.3, NP_000101.2 and NC_000001.10):
(rs67376798, c.2846A>T, p.(Asp949Val), g.97547947T>A), (rs56038477, c.1236G>A, p.(Glu412=), g.98039419C>T, in haplotype B3), (rs75017182, c.1129-5923C>G, g.98045449G>C, in haplotype 4 B3), (rs3918290, *2A, c.1905+1G>A, IVS14+1G>A, g.97915614C>G), (rs55886062, *13, c.1679T>G, p.(Ile560Ser), g.97981343A>C), (rs2297595, c.496A>G, p.(Met166Val), g.98165091T>C), (rs56293913, c.1129-15T>C, IVS10-15T>C, g:98039541A>G), (rs1801160, *6, c.2194G>A, p.(Val732Ile), g.97770920C>T), (rs17376848, c.1896T>C, p.(Phe632=), g.97915624A>G), (rs72549303, *3, c.1897delC/c.1898delC, p.(Pro633Glnfs), g.97915622delG), (rs72549309, *7, c.299_298delTCAT, p.(Phe100Serfs), g.98205971_98205974delATGA), (rs1801266, *8, c.703C>T, p.(Arg235Trp), g.98157332G>A), (rs1801265 + rs1801267, *9B, c.85T>C + c.2657G>A, p.(Cys29Arg)
+ p.(Arg886His), g.98348885G>A+ g.97564154C>T), (rs1801268, *10, c.2983G>T, p.(Val995Phe), g.97544627C>A), (rs72549306, *11, c.1003G>T, p.(Val335Leu), g.98058899C>A), (rs80081766, *12, c.62G>A, p.(Arg21Gln), g.98348908C>T), (rs78060119, c.1156G>T, p.(Glu386Ter), g.98039499C>A), (rs777425216, c.1651G>A, p.(Ala551Ser), g.97981371C>A), (c.1845G>T, p.(Glu615Asp)), (98205969, c.300C>A, (p.Phe100Leu)), (rs183385770, c.1024G>A, p.Asp342Asn, g.98058878C>T), (rs183385770, c.1025A>G, p.Asp342Asn, g.98058878C>T), (rs72549304, c.1475C>T, p.Ser492Leu, g.98015165G>A), (rs59086055, c.1774C>T, p.(Arg592Trp), g.97915746G>A), (g.(619762_619763)_(620801_620802)
dup), (rs1801158, *4, c.1601G>A, p.(Ser534Asn), g.97981421C>T), (rs1801159, *5, c.1627A>G, p.(Ile543Val), g.97981395T>C), (rs1801265, *9A, c.85T>C, p.(Cys29Arg), g.98348885G>A).
Additional phenotyping test when genotype is unable to predict phenotype
In contrast to the DPYD genotyping test, which aims to predict DPD enzyme activity, a DPD phenotyping test can be performed to measure the actual DPD enzyme activity. Possible methods to perform phenotyping are to measure the DPD enzyme activity in peripheral blood mononuclear cells (PBMCs) or to measure the uracil concentrations in plasma or urine.21 The average Caucasian DPD enzyme activity is 9.9±0.95 nmol/hour per mg protein.22 Less commonly performed methods include: 1) the 2-13C-uracil breath test,23 where 13C02 is measured, which is a product of 2-C13-uracil degradation by DPD and other enzymes involved in the katabolic route of pyrimidines; 2) the quantification of the uracil/dihydrouracil ratio in plasma, where endogenous substrates uracil and dihydrouracil are measured,24,25 although recently it was shown that uracil levels were superior to the dihydrouracil/uracil ratio as a predictor of severe toxicity;26 3) measurement the metabolism of a single dose of uracil.27 However, all DPD phenotyping tests have their limitations. Currently, the DPD enzyme activity measurements from PBMCs are considered the best developed DPD phenotyping test in The Netherlands.27,28
Supporting body of evidence
A detailed description of the methods used for literature collection, assessment and preparation of the gene-drug monograph has previously been published elsewhere.2,7 In brief,
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