Page 287 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Compound heterozygous DPYD variant allele carriers
as was calculated using frequencies of combinations of DPYD variants. Results for each combination of DPYD variants are shown in Table 5. With several million fluoropyrimidine users each year, thousands of patients worldwide are compound heterozygous for a subset of these four DPYD variants.
Table 3. Toxicity profiles of compound heterozygous DPYD variant allele carriers
Shown per patient are DPYD variants, fluoropyrimidine dose as a percentage of the regular dose, and experienced toxicity with this dose. All patients retrospectively identified as DPYD variants carrier received full doses and experienced severe (CTC-AE ≥3) toxicity. All patients prospectively identified as DPYD variant(s) carrier received dose reductions and experienced a maximum of CTC-AE grade 2 toxicity with the initial dose.
Patient #
1 2 3 4 5 6 7
DPYD variants
DPYD*2A + c.1236G>A DPYD*2A + c.2846A>T c.1236G>A + c.2846A>T DPYD*2A + c.2846A>T DPYD*2A + c.2846A>T DPYD*2A + c.1236G>A DPYD*2A + c.1236G>A
Dose (% of regular dose)
100%
50%
50%  70% 100%
50%
100%
100%
Toxicity (maximal CTC grade)
4
1─2
0 (on 50% dose)3 (on 70% dose) 5
0
4
3
Abbreviations: CTC-AE: common terminology criteria for adverse events.
Frequencies of compound heterozygous DPYD carriers with phasing information
In the GoNL database, genetic data from 496 subjects (fathers and mothers only) was reviewed. One subject was found who carried two DPYD variants. This subject was a carrier of the DPYD c.1236G>A and DPYD c.2846A>T variants, both of which were located on a single allele (in cis). Based upon the data in GoNL, the probability of having compound heterozygosity of the four DPYD variants is <0.2%.
In the 1000 Genomes database, data of 2,513 individuals was available. After the selection of unique, unrelated individuals, 407 individuals remained. One subject was found who carried two DPYD variants. This subject was a carrier of DPYD c.1236G>A and DPYD c.2846A>T, both of which were located on different alleles (in trans). Based upon the data in 1000 Genomes, the probability of having compound heterozygosity of the four DPYD variants is <0.3%.
In the LUMC clinical genetics database (exome trios LUMC), the analysis was restricted to the children, since this would allow phasing. None of the 433 children carried more than one DPYD variant, thus compound heterozygosity in this database is <0.2%.
Despite the low frequency, compound heterozygous patients were identified in all databases except the LUMC clinical genetics database. However, the low frequency did not allow to determine the probability of in cis or in trans phasing of variants in a patient.
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