Page 304 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 12
Abstract
Fluoropyrimidines are widely used anticancer drugs, but may lead to severe toxicity in up to 30% of patients. Prospective DPYD genotyping is increasingly used in clinical practice to predict and prevent severe toxicity, by means of initial dose reductions in DPYD variant allele carriers. While this strategy successfully reduces the incidence of severe toxicity, substantial toxicity remains that is not attributable to genetic variation in DPYD. A genome- wide association study (GWAS) was initiated to discover novel genetic variants associated with the onset of severe fluoropyrimidine-induced toxicity.
We conducted a GWAS in 1,146 patients treated with fluoropyrimidines who participated in the Alpe DPD study. Patients were genotyped using the Illumina Global Screening Array and data was imputed using the 1000 Genomes reference panel. The primary outcome was severe (grade ≥3) fluoropyrimidine-induced toxicity, compared to grade 0 or 1 fluoropyrimidine-induced toxicity. Variants were tested for association with severe fluoropyrimidine-induced toxicity using logistic, Cox, and ordinal regressions. A Polygenic Risk Score (PRS) was constructed by extracting all variants with p<0.01 in the association test.
1,101 patients passed the quality control (QC) analyses and 599 patients were included in the primary analysis. After imputation, 4,650,899 variants were included in the analysis. None of the genetic variants showed genome-wide significance (p<5x10-8). Six variants were suggestive (p<5x10-6) for the onset of severe fluoropyrimidine-induced toxicity. A PRS was constructed including 5,055 variants and predicted 62% of severe toxicity by non-genetic covariates alone and 96% by the combined analysis including covariates.
While no genome-wide significant variants could be identified, six variants were suggestive for the onset of severe toxicity in merely Caucasian patients. These variants are located outside of known fluoropyrimidine-pathway genes. Using a PRS consisting of 5,055 variants combined with clinical variables explained 96% of toxicity in this discovery cohort. This GWAS is one of the first attempts to identify variants predictive for fluoropyrimidine- induced toxicity and identified variants and the PRS require replication in an independent cohort.
Acknowledgements
The authors thank the Human Genotyping Facility of the Erasmus Medical Center for the execution of the genotyping and all participating centres of the NCT02324452 study for their help in including patients in the study.
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