The Roles of MTRR and MTHFR Gene Polymorphisms in Colorectal Cancer Survival

Abstract

Background: Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) and CRC survival. Methods: This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina’s integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms in MTRR and MTHFR in relation to overall survival (OS), disease-free survival (DFS) and CRC-specific survival. Results: The MTRR and MTHFR genes were associated with DFS and CRC-specific survival in CRC patients at the gene level. After multiple comparison adjustment, MTRR rs1801394 A (vs. G) allele was associated with increased DFS (p = 0.024), while MTHRT rs3737966 (G vs. A), rs4846049 (T vs. G), rs1476413 (A vs. G), rs1801131 (C vs. A), rs12121543 (A vs. C), rs1801133 (C vs. T), rs4846052 (T vs. C), rs2066471 (A vs. G) and rs7533315 (T vs. C) were related to worse CRC-specific survival. Additionally, significant interactions were seen among pre-diagnostic alcohol consumption with MTRR rs1801394, rs3776467, rs326124, rs162040, and rs3776455, with superior OS associated with those protective variant alleles limited to patients with alcohol consumption under the median. The MTHFR rs3737966 (G vs. A) allele seemed to be detrimental to CRC survival only among subjects with fruit intake below the median. Conclusions: Polymorphic variants in MTRR and MTHFR genes that code for key enzymes for folate metabolism may be associated with survival in patients with CRC. The gene-CRC outcome association seems modulated by alcohol drinking and fruit intake.

Personalized Medicine in Infant Population with Cancer: Pharmacogenetic Pilot Study of Polymorphisms Related to Toxicity and Response to Chemotherapy

“…In a previous publication from our group [22], with a totally different cohort of neuroblastoma patients, we already found that this variant was correlated with poorer overall survival in both normal and amplified MYCN patients. It is not clear yet if these results are through a direct effect of the enzyme on the chemotherapeutic drugs, or related to DNA methylation and or synthesis, or a combination of all, but recent literature find similar results in different adult and pediatric cancers [18,23,24].…”

Research Progress on <i>MTHFR</i> C677T and A1298C Gene Polymorphisms and Gastrointestinal Tumors

“…However, Baghad et al showed a statistically significant association between the MTHFR677T variant and the risk of sporadic colorectal carcinogenesis in a Moroccan population, CT genotype and its combination with TT genotype and allele T were associated with increased risk of CRC, but the pure-hybrid TT was not a protective factor. A recent study [49] showed that the MTHFR gene was associated at the genetic level with disease-free survival and CRC-specific survival in CRC patients, and the association of the gene with CRC outcome appeared to be modulated by alcohol consumption and fruit intake. Notably, Teng [42] and Haerian BS [50] studies presented a different view, stating that the MTHFR A1298C polymorphism was positively associated with susceptibility to CRC, which may be due to inconsistent genetic modeling.…”