Impact of Genetic Polymorphisms on the Metabolic Pathway of Vitamin D and Survival in Non-Small Cell Lung Cancer

Abstract

Vitamin D has been associated with risk, development, and progression of cancer. However, the genes involved in its metabolism are highly polymorphic, compromising its activity. The aim of this study is to evaluate the association between the gene polymorphisms involved in the metabolic pathway of vitamin D and survival in patients with non-small-cell lung cancer (NSCLC). The study was designed as an observational cohort which included 194 Caucasians patients from southern Spain with NSCLC. Real-time polymerase chain reaction was used to analyze the following polymorphisms: CYP27B1 rs4646536, rs3782130, and rs10877012; CYP24A1 rs6068816 and rs4809957; GC rs7041; CYP2R1 rs10741657; VDR rs1544410 (BsmI), rs11568820 (Cdx-2), rs2228570 (FokI), rs7975232 (ApaI), and rs731236 (TaqI). Progression-free survival (PFS) and overall survival were assessed. Cox regression showed that rs4646536 was associated with PFS in the general population (p = 0.0233) and in the non-resected NSCLC subgroup (p = 0.0233). In the resected NSCLC subgroup, rs11568820 was associated with OS (p = 0.0129) and rs7041 with PFS (p = 0.0447). In the non-resected NSCLC subgroup, rs6068816 was associated with PFS (p = 0.0048) and OS (p = 0.0089) and rs731236 and rs7975232 were associated with OS (p = 0.0005) and PFS (p = 0.0002), respectively. The other polymorphisms showed no effect on the results. The rs4646536, rs6068816, rs7041, rs11568820, rs731236, and rs7975232 polymorphisms are associated with survival in NSCLC and may have a substantial role as prognostic markers of the disease.

Vitamin D-Related Single Nucleotide Polymorphisms as Risk Biomarker of Cardiovascular Disease

“…Vitamin D can be obtained from 7-dehydrocholesterol after exposure to sunlight and through food [ 19 , 20 , 21 ]. Vitamin D is hydroxylated to 25-hydroxyvitamin D 3 (25(OH)D 3 ) in the liver and 1α-hydroxylated in the kidney, forming the active hormone 1,25-dihydroxyvitamin D 3 (1.25(OH) 2 D 3 ) [ 22 , 23 ].…”

Effect of Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway on Susceptibility to Non-Small-Cell Lung Cancer

“…Both cholecalciferol and ergocalciferol are ingested through the diet [ 8 ]. Both isoforms (vitamin D2 and D3) are transported in the bloodstream by being bound to VDBP (vitamin D binding protein), which carries the two precursors to the liver [ 12 ]. Here, the first hydroxylation takes place at position 25 through the action of the CYP2R1 or 25-hydroxylase enzyme.…”

“…Here, the first hydroxylation takes place at position 25 through the action of the CYP2R1 or 25-hydroxylase enzyme. This reaction produces calcidiol or 25-hydroxyvitamin D. This metabolite remains in the blood for longer, so serum vitamin D levels are determined by calcidiol [ 8 , 11 , 12 ]. This is followed by a second hydroxylation of the molecule in the kidney, through the action of the CYP27B1 or α-1-hydroxylase enzyme, resulting in the active form of vitamin D: 1,25(OH)2D [ 7 , 10 ].…”

“…Cells with high expression of VDR are sensitive to the antiproliferative activity of 1,25D3 [ 13 ]. Finally, vitamin D is degraded at mitochondrial level by the action of the CYP24A1 enzyme, preventing it from accumulating [ 11 , 12 , 14 , 15 ].…”

“…The genes that code for the enzymes involved in vitamin D metabolism ( GC , CYP2R1 , CYP27B1 , CYP24A1 , and VDR ) are highly polymorphic [ 12 , 16 ]. Single nucleotide polymorphisms (SNPs) in these genes can alter both the functionality of the synthesized enzymes and the expression of each gene, and may therefore play an essential role in the onset, progression, and prognosis of NSCLC [ 12 , 17 ].…”