Sara Salvador-Martín, Irene Taladríz-Sender, Paula Zapata-Cobo, Gina Hernández-Osio, Javier Soto-Alsar, José Luis Revuelta-Herrero, Pilar García-Alfonso, Fabienne Thomas, María Sanjurjo-Sáez, Luis A López-Fernández, Xandra García-González
The c.2766+3A>T variant leads to a non-functional DPD enzyme and is a likely cause of severe fluoropyrimidine-related toxicity. This variant should be considered deleterious.
BACKGROUND: Fluoropyrimidines are widely used for the treatment of solid tumours, but they carry a significant risk of severe toxicity in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.
CASE PRESENTATION: We describe a 50-year-old male with colorectal cancer who received adjuvant XELOX (oxaliplatin and capecitabine) and developed life-threatening grade 3-4 toxicities. Routine DPYD genotyping showed no pathogenic variants. Subsequent DPYD exon sequencing identified three heterozygous variants: c.1627A>G, c.2194G>A, and c.2766+3A>T. The latter, a rare intronic variant, was demonstrated to cause exon 21 skipping by mRNA analysis of peripheral blood mononuclear cells (PBMCs). The patient presented a profound DPD deficiency.
CONCLUSION: The c.2766+3A>T variant leads to a non-functional DPD enzyme and is a likely cause of severe fluoropyrimidine-related toxicity. This variant should be considered deleterious.