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Determinants of Folate Metabolism in Colorectal Cancer Patients and Healthy Individuals
Fabio Coppedè², Angela Lopomo², Francesca Migheli², Alessandra Failli³, Lidia Surace¹, Annalisa Legitimo³, Rita Consolini³, Roberto Spisni^*1, Lucia Migliore^2
1Department of Surgery, Medical, Molecular, and Critical Area Pathology, University of Pisa, Pisa, Italy, University of Pisa, Pisa, Italy; ²Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy, University of Pisa, Pisa, Italy; ³Department of of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, University of Pisa, Pisa, Italy

Folate metabolism, a complex pathway required for either the synthesis of DNA precursors or for DNA methylation reactions, has been frequently suggested to play a key role in colorectal cancer (CRC) pathogenesis. In the present study we collected 96 CRC individuals (55 males/41 females, mean age 71.04 years) and 96 healthy matched controls (53 males/43 females, mean age 70.86 years) to further investigate the determinants of folate metabolism in both CRC patients and healthy matched controls. All the individuals have been genotyped for nine biallelic polymorphism of genes involved in folate metabolism (MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, MTRR 66A>G, SLC19A1 80G>A, TYMS 28bp 2R/3R, TYMS 1494 6bp ins/del, DNMT3B -579G>T, DNMT3B -149C>T). In addition, we also measured plasma homocysteine (hcy), serum folate, and serum vitamin B12 levels in those subjects that were not taking drugs or supplements known to interfere with those parameters.
Multifactorial analysis of variance revealed significantly decreased serum folate (P=0.04) and plasma hcy (P=0.02) levels in CRC patients with respect to healthy matched controls. In addition, vitamin B12 levels had a significant effect on serum folate concentrations (P=0.04), whilst a significant contributor of plasma hcy levels was age at sampling (P=0.0001). Concerning the polymorphisms of metabolic genes, none of them showed significant different distributions between CRC patients and healthy controls. However, the MTRR 66A>G polymorphism was associated with serum folate levels in both CRC and healthy individuals (AA vs. GG, P<0.05), the SLC19A1 80G>A polymorphism showed a significant correlation with hcy levels in our population (GG vs. AA, P<0.05), and the DNMT3B -579G>T polymorphism resulted associated with serum vitamin B12 levels (GG vs. GT, P<0.05).
Present results suggest that complex interactions among folate, hcy, vitamin B12, and polymorphisms of metabolic genes, superimposed on age related declines, might be responsible of the impairments of folate metabolism in CRC patients.
The study was supported by Istituto Toscano Tumori (ITT) Prot. AOOGRT/325424/Q.80.110 16/12/2009.

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