Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas.
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 1p36.3 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.
Viel
A
A
Division of Experimental Oncology, Centro di Riferimento Oncologico, Aviano, Italy.
Dall'Agnese
L
L
Simone
F
F
Canzonieri
V
V
Capozzi
E
E
Visentin
M C
MC
Valle
R
R
Boiocchi
M
M
D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D015139:Blotting, Southern; D002277:Carcinoma / Q000737:chemistry / Q000201:enzymology / Q000235:genetics*; D002352:Carrier Proteins / Q000096:biosynthesis; D002872:Chromosome Deletion; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006579:Heterozygote; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D010051:Ovarian Neoplasms / Q000737:chemistry / Q000201:enzymology / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D013763:Tetrahydrofolates / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D010088:Oxidoreductases; D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D042965:Methylenetetrahydrofolate Reductase (NADPH2)