Author(s): Batoul Sadat Haerian [*] aff1 , Monir Sadat Haerian aff2 aff3
colorectal cancer; meta-analysis; MTHFR; polymorphism; susceptibility
Colorectal cancer (CRC) is the third leading cause of cancer death in both men and women. Approximately 950,000 patients are newly diagnosed each year [ 1 ]. CRC is a complex multifactorial disease contributed by genetic and environmental risk factors and their complex interaction [2 ]. Evidence has specified a large number of potential genes contributed to pathogenesis of CRC [3 ]. One hypothesis is that mutations in the genes of folate metabolism enzymes disturb this pathway and may result in folate insufficiency. Folate plays an important role in the biosynthesis of nucleotide precursors used for DNA synthesis and methylation of DNA, RNA and proteins [4 ]. MTHFR encoded by MTHFR gene is a key enzyme of folate metabolism process [5 ]. Over 91 original studies and 15 meta-analyses were conducted on the association of two exonic rs1801133 C[greater than]T (Ala222Val) and rs1801131 (Glu429Ala) polymorphisms of this gene with CRC in various populations, however, results are inconsistent (Figure 1 & Supplementary Table 1; see online at: www.futuremedicine.com/doi/suppl/10.2217/pgs.14.177) [6-20 ]. To derive a more precise estimation of these associations, we conducted a meta-analysis of rs1801133 and rs1801131 polymorphisms and their diplotypes related to the risk of CRC and also we systematically evaluated the previous meta-analyses of both polymorphisms in CRC.
The procedures of the systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, including the search and selection of studies, data extraction from the studies and meta-analysis (overall, subgroup, sensitivity, publication bias and meta-regression analysis) [21 ].
Search strategy & selection
Articles were sought by using the MeSH terms 'colorectal cancer,' 'colon cancer,' 'rectal cancer,' 'susceptibility,' 'polymorphism,' 'variant,' 'MTFHR ,' '5,10-Methylenetetrahydrofolate reductase,' 'Methylenetetrahydrofolate reductase,' 'rs1801133,' 'rs1801131,' 'rs1801133 C[greater than]T,' 'rs1801131 A[greater than]C,' 'Crs1801133T,' 'Ars1801131C,' 'Ala222Val,' 'Glu429Ala,' 'Arg594Gln,' 'A222V,' 'E429A,' 'Q594R,' '677 C[greater than]T,' '665 C[greater than]T,' '1286 A[greater than]C,' '1298 A[greater than]C,' '1793 G[greater than]A,' '1781 G[greater than]A' and 'susceptibility' in the major bibliographical databases including MEDLINE, Scopus, Embase, Cochrane Library and ScienceDirect without language limitation, the last search being updated in June 2014. The reference lists were hand searched for other relevant publications.
Studies that determined the distribution of the MTFHR rs1801133 and rs1801131 genotype in unrelated patients and healthy controls were eligible for inclusion in the meta-analysis. Publications were eligible for meta-analysis if they met the following inclusion criteria: study had been done in patients with colon cancer and/or with rectal cancer or with both and in controls; and genotype frequency data were available for both case and control groups. Major exclusion criteria were as follows: controls were related to patients; data duplicated those of previous publications and the genotype data of the study was not extractable; data from familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer.
The following characteristics were collected from each study: first author's surname, year of publication, ethnicity of patients, numbers of patients and controls...