Association between miRNA expression profiles and polymorphisms of dihydropyrimidine dehydrogenase drug‑metabolizing gene in patients with colorectal cancer receiving 5‑fluorouracil

Abstract

5‑Fluorouracil (5‑FU) is widely used for colorectal cancer (CRC) treatment. Its administration is challenged by wide variability in patient toxicity. Genetic polymorphisms in dihydropyrimidine dehydrogenase (DYPD) and circulating microRNAs (miRNAs) are promising biomarkers to predict 5‑FU‑associated toxicity. The present study aimed to assess the association between miRNA expression profiles, three DPYD polymorphisms (85T>C, 1627A>G, 1896T>C) and hematological toxicity in patients with CRC receiving 5‑FU. A total of 48 patients with CRC treated with 5‑FU‑based regimens were prospectively enrolled. Genotyping for DPYD 85T>C, 1627A>G and 1896T>C was performed by TaqMan Realtime PCR. Hematological toxicity was assessed by Common Terminology Criteria for Adverse Events v5.0 across two chemotherapy cycles. In a subset (n=9 for 85T>C; n=6 for 1896T>C), plasma levels of 43 candidate miRNAs related to 5‑FU metabolism were quantified using a custom miRNA PCR array. The variant allele frequencies of DPYD were 0.14 for both 85T>C and 1896T>C, and 0.17 for 1627A>G. Although no associations were significant, carriers of 85T>C exhibited a higher incidence of grade ≥1 anemia in cycle two (69.2 vs. 40.0%, TC and CC; P=0.070). No significant trends were observed for other toxicities. miRNA profiling revealed that 20 miRNAs were differentially expressed in 85T>C carriers (9 up‑ and 11 downregulated) and 14 miRNAs in 1896T>C carriers (5 up‑ and 9 downregulated) vs. wild‑type (P<0.05). The present findings suggest that the DPYD 85T>C polymorphism may predispose patients with CRC to cumu‑ lative hematological toxicity and is associated with distinct plasma miRNA signatures. Integration of DPYD genotyping with miRNA profiling warrants further investigation as a strategy to optimize 5‑FU dosing and minimize toxicity in CRC.