A Quantitative Risk Assessment of Fluoropyrimidine Toxicity Without Preemptive DPYD Screening in Brazil Compared to Global Standards
Fernando Augusto Siuta dos Santos, Pedro Dytz Marin, Giulia Scain, Isabela Alicia Fink, Julia Loureiro Chaves Cé, Stéphanie Klein Brum, Mariana Weremeier Weber, Martina de Sá, Rafaela Sumienski Girardi, Solana de MeloPURPOSE
This study quantifies the clinical risk of fatal fluoropyrimidine toxicity in Brazil due to the absence of preemptive DPYD genotyping. While the European Medicines Agency (EMA) mandates screening to ensure patient safety, the lack of similar policies in low- and middle-income countries (LMICs) creates a preventable health crisis.
METHODS
Allele frequencies (AF) for three confirmed highly penetrant DPYD pathogenic variants were extracted from gnomAD (v4.1.1). Cumulative AF was calculated for Admixed American (AMR) and Non-Finnish European (NFE) populations. Carrier frequency (CF) was estimated using the Hardy-Weinberg approximation for rare alleles. To translate genetic metrics into public health risk, the AMR CF was multiplied by the Brazilian National Cancer Institute (INCA) estimate of 45,630 incident CRC cases per year, assuming standard fluoropyrimidine exposure and no baseline genotyping rate.
RESULTS
Individual variant distribution showed significant global variance; notably, variant 1-97740456-G-A presented a higher AF in the AMR cohort (0.0001167) than in NFE (0.0000881). Cumulatively for the three analyzed variants, gnomAD data yielded AFs of 0.0002984 (NFE), 0.0001667 (AMR), and 0.0000665 (AFR). The derived CFs are 0.059% (NFE), 0.033% (AMR), and 0.013% (AFR). Applying the AMR CF (0.0003334) to INCA epidemiological data projects a minimum baseline of 15 incident CRC patients annually carrying these specific, life-threatening alleles in Brazil. While the NFE population presents the highest genetic CF, mandatory EMA screening protocols reduce their clinical risk to near zero. Conversely, the 0% screening baseline in Brazil translates to a 100% unmitigated exposure rate for the AMR and AFR carrier populations.
CONCLUSION
We identified a definitive, quantifiable cohort of Brazilian CRC patients exposed to critical fluoropyrimidine toxicity annually due to three specific high-penetrance DPYD variants. The global comparison highlights a critical health disparity: while European cohorts carry a higher baseline genetic burden for these specific alleles, the absence of pharmacogenomic infrastructure in LMICs renders the AMR and AFR populations clinically more vulnerable to preventable iatrogenic harm.