C677T single nucleotide polymorphism of methylenetetrahydrofolate reductase gene and colorectal cancer

Abstract

Introduction: Methylenetetrahydrofolate Reductase Gene (MTHFR) is the most critical enzyme in folate-metabolizing pathway. Its C677T SNP (rs1801133) is the most important one regulating the function of this enzyme and it has been linked to cell cycle progression, cell growth, many types of cancers including colorectal cancer (CRC), drug metabolism, and inflammation are associated with response to chemotherapy. Studies suggest specific polymorphisms associated with response to chemotherapeutic agents and also predict toxicity to treatment. We studied the association between C677T single nucleotide polymorphism of MTHFR gene and colorectal cancer and treatment related toxicity. Methods: This study was carried out by cooperation between Medical Biochemistry, General Surgery and Clinical Oncology & Nuclear Medicine Departments, Faculty of Medicine, Menoufia University in the period from May 2015 to December 2015. It was conducted on 70 subjects classified into the following groups: Group I: included 50 CRC patients (26 males and 24 females); 39 cases colon cancer and 11 cases rectal cancer. Cancer patients group was subdivided into 2 subgroups: -Ia: included 29 CRC patients under 5-flurouracil (5-FU) based chemotherapy, Ib: included 21 CRC patients under follow up and Group II: included 20 healthy controls (11 males and 9 females). Laboratory investigations including detection of MTHFR gene C677T SNP (rs1801133) by real time PCR using the TaqMan allelic discrimination Assay technique. Assessment of toxicity in fluorouracil based chemotherapy treated patients was based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTC AE) version 4.0 Results: Results showed that T/T genotype and the T allele of MTHFR C677T was significantly higher in CRC patients compared with healthy controls (p=0.01) and (p=0.009) respectively. A significant association was found between T allele and risk of developing CRC (OR=1.34, CI 95%=1.10-1.64). According to dukes stage: There was a significant statistical difference regarding to lymph node positivity (Dukes C) was found among different C677T genotypes, also a significant statistical difference in presence of distant metastasis (Dukes D) among different C677T genotypes, where TT genotype was significantly higher with both. There was non-significant statistical difference regarding to tumor grade and size among different C677T genotypes. In subgroup analysis: in CRC patients treated with 5 FU based chemotherapy (5FU/leucovorin, CAPEOX, FOLFOX, FOLFIRI protocols and Capecitabine) there was a significant statistical difference between CC and TT genotypes regarding incidence of diarrhea with 20% of TT genotype having grade I&II toxicity while 40% having grade III while neither CT nor CC genotype patients developed grade III diarrhea and also there was non-significant statistical difference among three differentC677T genotypes regarding vomiting, oral mucositis and fever neutropenia. Conclusion: It was concluded that C677T polymorphism in the MTHFR gene might be a candidate risk factor for developing CRC. Individuals carrying T allele of C677T MTHFR gene have increased risk of developing CRC, while individuals carrying C allele demonstrated a protective effect for developing CRC. In CRC patients receiving Fluorouracil based chemotherapy Diarrhea was higher among TT genotype carriers.