Impaired vitamin D activation and association with CYP24A1 haplotypes in differentiated thyroid carcinoma.

BACKGROUND: Common polymorphisms of the vitamin D receptor gene have been reported to affect the risk of breast, colon, prostate, and differentiated thyroid cancer (DTC), but polymorphisms within the genes of vitamin D metabolizing enzymes have not been studied in DTC. The aim of the present study was to investigate the genes for vitamin D enzymes in patients with DTC and healthy controls (HC) as well as the vitamin D (25-hydroxyvitamin D(3), and 1,25-hydroxyvitamin) status.

METHODS: German patients (n=253) with DTC (papillary thyroid carcinoma [PTC] and follicular thyroid carcinoma [FTC]) and HC (n=302) were genotyped for polymorphisms within the vitamin D metabolizing enzymes such as 25-hydroxylase (CYP2R1[rs12794714, rs10741657]), 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1[rs10877012, rs4646536]), and 25-hydroxyvitamin D 24-hydrolase (CYP24A1[rs927650, rs2248137, rs2296241]). Furthermore, the 25-hydroxyvitamin D(3) [25(OH)D(3)] and 1,25-hydroxyvitamin [1,25(OH)(2)D(3)] plasma levels were measured by a radioimmunoassay.

RESULTS: There was no difference in the genotypes; however, the CYP24A1 haplotype analysis showed that rs2248137C/rs2296241A (13.1% vs. 19.1%; corrected p [pc]=0.04) was less frequent in the PTC, whereas the haplotypes rs2248137C/rs2296241G (56.0% vs. 41.9%; pc=0.03), rs927650C/rs2296241G (22.5% vs. 8.4%; pc=1.6×10(-3)), and rs927650C/rs2248137C/rs2296241G (21.1% vs. 7.3%; pc=1.5×10(-3)) were more frequent in the FTC compared with HC. Furthermore, if patients and controls were grouped according to four 25(OH)D(3) categories (severely deficient, deficient, insufficient, and sufficient), then the patients with both DTC subtypes had significantly lower levels of circulating 1,25(OH)(2)D(3), especially in the group with a deficient 25(OH)D(3) status compared with the controls. Although the polymorphisms showed no differences stratified for the four 25(OH)D(3) categories, the activation status by 1,25(OH)(2)D(3) differed significantly depending on the genotypes of the investigated CYP24A1 polymorphisms.

CONCLUSIONS: A higher risk for DTC is conferred by haplotypes within the CYP24A1 gene, low circulating 25(OH)D(3) levels (deficiency), and a reduced conversion to 1,25(OH)(2)D(3). These results confirm and extend previous observations and also support a role of the vitamin D system in the pathogenesis of DTC. How deficient 25(OH)D(3) levels in combination with certain CYP24A1 haplotypes affect vitamin D activation is the subject of future studies.