Page 282 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 11
Patients
Data and DNA from patient cases carrying multiple DPYD variants were collected. Patients were identified either after development of severe toxicity from fluoropyrimidine-containing therapy, by additional retrospective genotyping in a clinical trial (clinicaltrials.gov identifier NCT00838370),13 or prior to treatment in routine clinical care. The study was reviewed and approved by the institutional review board of the Leiden University Medical Center (LUMC, G18.15). Patient data from the electronic medical records was handled following the codes of proper use and proper conduct in the self-regulatory codes of conduct.22 Toxicity to fluoropyrimidine-containing therapy was graded by the treating physicians using the National Cancer Institute CTC-AE version 4.03,23 and severe fluoropyrimidine-induced toxicity was defined as CTC-AE grade ≥3. In some cases, additional patient material to determine the phasing of the DPYD variants was collected. In these cases, additional patient consent was obtained.
Wild-type
Heterozygous
Homozygous
Compound Heterozygous (in trans)
Compound Heterozygous (in cis)
Figure 1. Illustration of zygosity and clinical interpretations
A wild-type patient carries no variants, resulting in normal activity alleles (green). A heterozygous patient carries one variant, resulting in one reduced or inactive allele (red) and one active allele (green). A partly reduced enzyme activity is expected, since there is still one active allele left. For homozygous patients, both variants result in a reduced or inactive allele (red). Depending on the effect of the variants on the protein, a reduced or absent enzyme activity is expected. Compound heterozygous patients can carry variants on different alleles (in trans) or on one allele (in cis), resulting in differences in enzyme function, either like that of a heterozygous patient or a homozygous patient. Stars represent variants; boxes represent alleles.
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