Genetic sequence variants in vitamin D metabolism pathway genes, serum vitamin D level and outcome in head and neck cancer patients

Abstract

Although some studies have reported associations between serum vitamin D level and prognosis in several cancers, others have found associations between genetic sequence variants (GSVs) in the vitamin D metabolism pathway genes and outcomes in various cancers including head and neck cancer (HNC). We comprehensively evaluated the association and interaction of GSVs in vitamin D metabolism pathway genes and their regulatory effects on circulatory serum vitamin D level in HNC outcome. We systemically evaluated the association of 89 tagging and candidate-based GSVs in six major vitamin D metabolism pathway genes (VDR, GC, CYP24A1, CYP27A1, CYP27B1 and CYP2R1) and the circulating serum vitamin D level with overall survival (OS) and second primary cancer (SPC) in 522 Stages I-II radiation-treated patients with HNC. For OS: median follow-up time was 8 years; for SPC, 4.4 years. The most common subsite was the larynx (84%). Three hundred and twelve patients were alive at the end of follow-up for OS. SPCs were diagnosed in 108 patients and were primarily of lung (46%). Serum vitamin D levels were significantly lower in patients carrying the minor alleles of GC:rs4588 and CYP2R1:rs10500804. CYP24A1:rs2296241 was significantly associated with OS and CYP2R1:rs1993116 was with SPC. These two GSVs remained significantly associated after adjusting for serum vitamin D level and important clinical factors. GSVs in the vitamin D metabolism pathway genes were associated with disease outcomes in HNC patients; however, these GSVs are different from those affecting serum vitamin D levels. In contrast, lower levels of serum 25(OH)D have been associated with an increased risk of oral cavity and esophageal, 3 colorectal, 4,5 breast, 6 ovarian 7 and prostate 8 cancers. One study found subnormal 25(OH)D (<37.5 nmol/L) in a significant proportion (45%) of patients with head and neck cancer (HNC) in a Finnish population, 9 while other studies found no association of serum vitamin D level with HNC risk 10 and HNC outcome. 11 Inherited genetic sequence variants (GSVs) that also influence the circulating 25(OH)D level could serve as biomarkers to investigate the association of serum vitamin D level with disease outcome. Results from previous twin and family studies suggest that GSVs in common vitamin D metabolism pathway genes may contribute to the variability of vitamin D level. 12,13 Genome-wide association studies have found the regulatory role of GSVs in vitamin D metabolic pathway genes and their association with circulating vitamin D level. 14,15 Furthermore, one study showed that the presence of detrimental Key words: head and neck cancer, serum vitamin D level, genetic sequence variant, overall survival, second primary cancer Additional Supporting Information may be found in the online version of this article.

CYP24A1andCYP27B1Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence

“…In the present study, increasing copies of the G allele in rs2296241 were related to increased odds for lesions with villous histology, a finding with similar directionality to another report showing that increasing copies of the G allele were associated with reduced overall survival among patients with head and neck cancers (41). In contrast, results of other studies have indicated that the presence of the G allele is protective, with reports showing that rs2296241 heterozygotes were at reduced risk for oral cancer (42), and for prostate-cancer specific deaths (43).…”

Association of vdr, cyp27b1, cyp24a1 and mthfr gene polymorphisms with oral lichen planus risk

“…The similar trend was previously observed in oral cancer cohort [21], while a recent study on head and neck cancer patients reported that rs2296241 heterozygous and mutated genotypes had worse overall survival [33]. However, whether the wild type form of CYP24A1 gene polymorphism rs2296241 could be associated with the OLP progression to oral cancer demands further prospective investigations on a larger cohort of patients.…”

Vitamin D-Related Gene Polymorphisms, Plasma 25-Hydroxy-Vitamin D, Cigarette Smoke and Non-Small Cell Lung Cancer (NSCLC) Risk

“…This might be attributed to CYP24A1 being increased in NSCLC tumors. Several studies have already examined the gain of 20q in gastro-esophageal junction [40], colon [41], breast [42], prostate [43], head and neck [44] as well as lung tumors [45,46]. Kong et al reported that CYP24A1 can reduce the 25(OH)D level and potentially increase NSCLC risk in cases with kinds of CYP24A1 polymorphisms [47].…”