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The association of polymorphisms in folate-metabolizing genes with response to adjuvant chemotherapy of colorectal cancer

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Abstract

Background

Colorectal cancer (CRC) is one of the major health issues worldwide. 5-Fluorouracil (5-FU) is a cornerstone of chemotherapy for CRC and the major targets of 5-FU are folate-metabolizing enzymes.

Methods

A total of 103 CRC patients with complete clinical data were included in this prospective cohort study. Genotyping was performed using polymerase chain reaction (PCR) followed by sequencing. Using Kaplan–Meier curves, log-rank tests, and Cox proportional hazard models, we evaluated associations between functional polymorphisms in four genes MTHFR (1298A>C and 677C>T), DPYD (496A>G and 85T>C), DHFR 19 bp del, and MTR (2756 A>G) with disease-free survival (DFS).

Results

The minor allele frequencies of MTHFR 1298A>C, MTHFR 677C>T, DPYD 496A>G, DPYD 85T>C, DHFR 19 bp del, and MTR 2756 A>G were 0.364, 0.214, 0.116, 0.209, 0.383, and 0.097, respectively. CRC patients carrying the homozygous GG genotype in DPYD 496A>G had 4.36 times shorter DFS than wild-type AA carriers, (DFSGG vs AA: 8.0 ± 4 vs 69.0 ± 10 months; HR 4.36, 95% CI 1.04–18; p = 0.04). Moreover, female carriers of homozygous CC genotype of DPYD 85T>C had shorter DFS compared to either heterozygous or wild-type genotypes, and were 12.7 times shorter than wild-type TT carriers (DFSCC vs TT: 5.0 ± 1.5 vs 42.0 ± 7.6 months; HR 12.7, 95% CI 2.2–71.4; p = 0.004). However, there were no significant associations with the other studied polymorphisms.

Conclusion

Genetic polymorphism in DPYD seems to be associated with DFS in CRC patients receiving an adjuvant regimen of 5-FU/capecitabine-based chemotherapy. Further studies are needed to verify these findings.

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Acknowledgements

Our greatest appreciation goes to the staff of oncology department of Al-Bashir hospital from top consultants to the last member of the nursing staff for their care and support. Our sincere appreciation goes to Muhammed Yousef and Khalil Majdalawi for their support.

Funding

This study was funded by the University of Jordan.

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Authors and Affiliations

  1. Department of Biopharmaceutical and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan

    Al-Motassem Yousef, Mohammed Zawiah, Shorouq Al-Yacoub, Taha Kadi, Dua’ a Tantawi & Hanguin Al-Ramadhani

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  1. Al-Motassem Yousef
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  2. Mohammed Zawiah
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  3. Shorouq Al-Yacoub
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Corresponding author

Correspondence to Al-Motassem Yousef.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The protocol of the study was approved by the institutional review board (IRB) of Al-Bashir Hospital (IRB no. 1652, 3/6/2014) and Jordan University Hospital (IRB no. 354, 4/2/2014), and conducted in concordance with the principles of the Declaration of Helsinki 1964 and its later amendments or comparable ethical standards.

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Each patient provided their written informed consent.

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Yousef, AM., Zawiah, M., Al-Yacoub, S. et al. The association of polymorphisms in folate-metabolizing genes with response to adjuvant chemotherapy of colorectal cancer. Cancer Chemother Pharmacol 82, 237–243 (2018). https://doi.org/10.1007/s00280-018-3608-6

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