DPYD and TYMS polymorphisms as predictors of 5 fluorouracil toxicity in colorectal cancer patients

Abstract

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death. 5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for CRC. Our objective was to determine the genotypic frequency of polymorphisms affecting dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthetase (TYMS) genes and to correlate the genetic profile with the toxicity due to 5-FU, also considering nongenetic factors. This is a prospective study that involved 66 patients. We extracted DNA by salting out methods. We carried out the genotyping of the different polymorphisms by simple PCR for the TYMS 5'UTR and by PCR-RFLP for DPYD: 1905 + 1 G > A, 85 T > C, 496 A > G, 1679 T > G, c.483 + 18G > A and the TYMS: 5'UTR VNTR, 5'UTR G > C and 3'UTR. The study of the association of DPYD and TYMS polymorphisms with the various signs of toxicity under 5-FU revealed that the polymorphisms 496 A > G were significantly associated with hepatotoxicity: OR = 3.85 (p = 0.04). In addition, 85 T > C was significantly associated with mucositis and neurotoxicity: OR = 4.35 (p = 0.03), OR = 3.79 (p = 0.02). For TYMS, the only significant association we observed for 5'UTR with vomiting: OR = 3.34 (p = 0.04). The incidence of adverse reactions related to 5-FU appears to be influenced in patients with CRC by the identified DPYD and TYMS gene polymorphisms in the Tunisian population.

Keywords:

• Pharmacogenetics
• biomarkers
• pharmacokinetic
• personalized medicine
• response
• thymidylate synthetase
• dihydropyrimidine dehydrogenase

Author contributions

This study was supervised by Asma Omezzine, Ali Bouslama, and Slim ben Ahmed. Yassine Khalij designed the study. Yassine Khalij and Sana Chouchene recruited the patients. Yassine Khalij and Imtinen Belaid obtained the data. Yassine Khalij performed the genotyping. Asma Omezzine and Yassine Khalij performed the statistical analysis and the interpretation of the data. Yassine Khalij wrote the manuscript. Asma Omezzine, Dorra Amor, and Nabila Ben Rejeb provided a critical review of the manuscript

Ethics approval

The study protocol was approved by the local ethics committee of the Farhat Hached University Hospital, Sousse, Tunisia.

Consent to participate: all patients signed specific written informed consent for the relevant pharmacogenetic analysis.

Acknowledgments

We thank the Tunisian Ministry of Higher Education, Scientific Research and Technology, and the Ministry of Health for their generous support. We are grateful to all the members of the Biochemistry laboratory of Sahloul University Hospital.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was funded by grants from the Tunisian Ministry of Higher Education, Scientific Research and Technology, and the Ministry of Health.