Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas

Abstract

Summary The high-affinity folate-binding protein (FBP) is primarily involved in the uptake of the 5-methyltetrahydrofolate, and its expression may be physiologically regulated by the intracellular folate content. The overexpression of FBP on the cell surface of ovarian carcinoma cells may be responsible for an increased folate uptake. We tested the hypothesis of the existence of a defect in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) in ovarian tumours that could cause reduced intracellular regeneration of the 5-methyltetrahydrofolate and induce increased FBP expression. No sequence mutations were found in the MTHFR gene, but allelic deletions of this gene were frequently detected in ovarian tumours (59%). Chromosomal losses appeared to be confined to the 1 p36.3 region to which the MTHFR gene maps. Although it cannot be stated that MTHFR is the target gene of the chromosomal loss involving the 1p36.3 region, a correlation between loss of heterozygosity at this locus and decrease in MTHFR activity was shown, suggesting a role of these allelic deletions in generating a biochemical defect in folate metabolism. Further studies are needed to assess further the relationship between MTHFR and FBP overexpression, but the demonstration of the alteration of a key metabolic enzyme of the folate cycle in a subset of human ovarian tumours is in accordance with the hypothesis of an altered folate metabolism in these neoplasias and might be exploited for therapeutic purposes.

Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors

“…Hypermethylation of IGSF4 was described in cervical (Li et al, 2005) and pancreatic (Jansen et al, 2002) cancers. MTHFR had not been previously shown to be hypermethylated in ovarian cancers, but it had been linked to ovarian carcinogenesis by loss of heterozygosity (Viel et al, 1997).…”

Antisense inhibition of methylenetetrahydrofolate reductase reduces survival of methionine-dependent tumour lines

“…We have recently demonstrated that MTHFR undergoes 15 -20% LOH in colorectal tumours (Pereira et al, 1999); LOH for MTHFR may be as high as 45 -50% in ovarian tumours (Viel et al, 1997). Treatment of two neuroblastoma cell lines and two breast carcinoma cell lines showed significant decreases in cell survival after treatment with 400 nM of EX5 compared to control oligo treated cells.…”

Analysis of the MTHFR 1298A→C and 677C→T polymorphisms as risk factors for neural tube defects

“…The identification of a second polymorphism within the MTHFR gene i.e., 1298A fi C (E429A) (Viel et al 1997;van der Put et al 1998) and its apparent association with decreased enzyme activity (van der Put et al 1998;Weisberg et al 1998Weisberg et al , 2001) has led to several association studies investigating the MTHFR 1298A fi C polymorphism and NTDs. Results from these studies have been inconsistent and Yamada et al (2001) found no difference in enzyme activity of 1298A fi C variants.…”