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The prevalence of 2R/2R  TYMS  genotype is variable but estimated to be around 20–30% in Caucasians. The clinical relevance of  TYMS 2R/2R  genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of  2R/2R TYMS  genotype.    Methods  Between 2011 and 2018, 126 patients were genotyped for  TYMS . FrAEs were graded according to CTCAE version 5.0. Fisher’s exact test was used for statistical analysis.    Results  The prevalence of  TYMS 2R/2R  genotype was 24.6%. Among patients with TYMS genotypes ( N  = 71) that predict decreased TS expression,  2R/2R TYMS  genotype was the most common  TYMS  genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression ( N  = 55), 12 patients had grade 3–4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression ( N  = 71), 30 patients had grade 3–4 FrAEs (42%) ( p  = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with  TYMS 2R/2R  genotype had grade 3–4 FrAEs ( p  = 0.0039) and 15 out 40 patients (38%) with  TYMS 2R/3RC  and  TYMS 3RC/3RC  genotype had grade 3–4 FrAEs ( p  = 0.1108).    Conclusion  The prevalence of  TYMS 2R/2R  genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of  TYMS  gene that predicts decreased TS expression due to  2R/2R  variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.

pharmacogenomics journal

The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens