Page 64 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
renewed recommendation is given following newly published articles.
Translation of genotype to predicted phenotype
The DPWG has concluded that four variants have sufficient evidence to be implemented into clinical care: DPYD*2A (IVS14+1G>A), DPYD*13 (c.1679T>G), c.2846A>T and c.1236G>A (in linkage disequillibrium with c.1129-5923C>G). The current guideline only reports recommendations for these four variants; no recommendations are provided for other variants in DPYD or other genes. The results of this genotyping panel can be used to predict a patient’s phenotype, i.e. the DPD enzyme activity. This predicted DPD activity can be expressed as the DPYD-gene activity score, which ranges from 0 (no or virtually no DPD enzyme activity) to 2 (normal DPD enzyme activity due to homozygosity for fully functional alleles, both assigned an activity score 1). The gene activity score is a sum of the two activities of protein isoforms expressed from both alleles. The development of the gene activity score is published elsewhere.20
The included variants are those for which substantial and sufficient evidence on the relation to severe toxicity has been established. It is a limitation to restrict to these four variants, as other variants may influence DPD activity as well. However, not all variants having a possible effect on DPD enzyme activity may have been identified yet or evidence for identified variants is insufficient. Therefore, this may result in the incorrect prediction of the DPD enzyme activity. Another limitation is that currently used genotyping methods are unable to determine the allelic location of the variants, but only the dichotomous presence or absence of the variant. This becomes a limitation when two or more different genetic variants are identified in a patient. In this case, either both genetic variants may be on the same allele, resulting in a genotype with one fully functional allele and one reduced functionality allele, or alternatively, both genetic variants may reside on different alleles, resulting in two alleles with inactive or reduced functionality. The latter is more likely to occur. The total gene activity score, however, differs between these cases. When the DPD enzyme activity cannot be predicted correctly, an additional phenotyping test is required to determine the DPD enzyme activity. The relationship between genotype result and predicted phenotype in patients carrying no variants or one or more variants leading to decreased DPD enzyme activity are shown in Supplementary Table 3. The frequency of individuals carrying two or more of four variants considered in the current guideline is rare, but can be assigned a gene activity score. A complete genotype to predicted phenotype translation table can be found in Supplementary Table 4, which can be used to program the translation of genotype results into predicted phenotypes in laboratory information systems.
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