Gene Polymorphisms Involved in Folate Metabolism and DNA Methylation with the Risk of Head and Neck Cancer

Asian Pac J Cancer Prev. 2020 Dec 1;21(12):3751-3759. doi: 10.31557/APJCP.2020.21.12.3751.

Abstract

Background: Folate is essential for DNA synthesis, repair, and methylation. Polymorphisms in genes associated with folate metabolism may alter these processes and, consequently, modulate cancer development.

Aim: We aimed to assess DNMT3B -149C/T (rs2424913), DNMT3B -283T/C (rs6087990), DNMT3B -579G/T (rs2424909), DHFR 19-pb ins/del (rs70991108), SHMT1 1420C/T (rs1979277), and TYMS 28-bp tandem repeat (rs34743033) polymorphisms with risk of head and neck cancer.

Methods: A case-control study was conducted in 1,086 Brazilian individuals. Real-time and conventional polymerase chain reactions-PCR were performed for genotyping the polymorphisms.

Results: The single nucleotide polymorphism (SNP), DNMT3B -283T/C, revealed a higher risk of head and neck squamous cell carcinoma (HNSCC) when compared with the C group in the codominant (p < 0.001), dominant (p <0.001), and overdominant (p= 0.001) models for T/C and C/C genotypes. DNMT3B -149C/T and DNMT3B -579G/T revealed no association between groups in any model. The DHFR 19-pb ins/del polymorphism protected against HNSCC development compared to the C group by the codominant (p < 0.001), dominant (p < 0.001), and overdominant (p < 0.001) models. In the TYMS, the 3R/3R genotype had a protective effect against HNSCC development compared with the C group by the recessive models (p= 0.009). In contrast, SHMT1 1420 C/T presented no association between the HNSCC and C groups. DHFR 19-pb ins/del polymorphisms protected against oral cavity cancer (p= 0.003), and only TYMS-28 3R/3R decreased the risk of tumor progression (p= 0.023). In the Kaplan-Meier curve, an association was found between DHFR ins/ins and TYMS -28 3R carriers with respect to relapse-free time; further, DNMT3B -579 T and TYMS-28 2R/2R carriers had longer survival times.

Conclusion: DNMT3B -283T/C is associated with higher risk, whereas DHFR 19-pb ins/del and TYMS 28 3R/3R protect against head and neck cancer. We also highlighted the association of TYMS 3R/3R genotype carriers with relapse-free cancer protection and survival time.

Keywords: DNA Methylation; Folate; Polymorphism; head and neck cancer.

MeSH terms

  • Biomarkers, Tumor / analysis
  • Brazil / epidemiology
  • Case-Control Studies
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methylation*
  • DNA Methyltransferase 3B
  • Female
  • Folic Acid / metabolism*
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Head and Neck Neoplasms / epidemiology*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Promoter Regions, Genetic
  • Risk Factors
  • Survival Rate
  • Tetrahydrofolate Dehydrogenase / genetics*
  • Thymidylate Synthase / genetics*

Substances

  • Biomarkers, Tumor
  • Folic Acid
  • Tetrahydrofolate Dehydrogenase
  • DNA (Cytosine-5-)-Methyltransferases
  • TYMS protein, human
  • Thymidylate Synthase