Personalized therapy: the crucial role of the DPYD c.2194G>A (V732I) allele in the treatment of colorectal cancer patients candidates for therapy with fluoropyrimidines

Abstract

5-Fluorouracil (5FU) is a chemotherapeutic agent belonging to the class of antimetabolite drugs, which exert a toxic action causing death of neoplastic cells. 5FU is mostly used as a standard treatment for colorectal cancer; the development of toxicity phenomena is related to the partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), limiting factor of the catabolism of fluoropyrimidines. Only 3-5% of 5-FU is converted to an active metabolite, while 85% of the drug is inactivated by DPD to 5-fluoro-dihydrouracil (5-FDHU). A reduced enzymatic activity of the DPD can be the cause for the presence of adverse drug reactions and toxicity in the patient, with multiorgan involvement, which can sometimes lead to death. The variants of the DPYD gene recommended by the AIOM (Associazione Italiana di Oncologia Medica)guidelines are: DPYD*2A (IVS14+1G>A, c.1905+1G>A); DPYD*13 (c.1679T>G); DPYD c.2846A>T, D949V; DPYD c.1236G>A (HapB3); DPYD c.2194G>A (V732I).Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and should not be treated with fluoropyrimidines, but this is a rare condition; while patients with partial deficiency should be treated with a reduced dose of the drug. Before starting treatment it’s crucial to determine the genetic profile of the patients candidates to therapy with fluoropyrimidines. In our cohort of the 370 samples analyzed by Real Time PCR, 294(~80%) are wild type for each variant screened. : DPYD c.2194G>A (V732I) alleleis significantly represented in the population examinated: considering the 15% reduction in drug administration imposed by this genotype, molecular profiling is essential before starting therapy with 5FU.In our study we also found a rare variant DPYD F632F rs17376848 c.1896 T> C in a patient, whose relevancefor therapeutic purposes is currently of uncertain significance.