Polymorphisms of Genes Related to Function and Metabolism of Vitamin D in Esophageal Adenocarcinoma.

ABSTRACT

PURPOSE: The vitamin D receptor (VDR) endocrine system has emerged as an endogenous pleiotropic biological cell regulator with anti-neoplastic effects on breast, colorectal, and prostatic adenocarcinomas. We studied the association of gene expression, polymorphisms of VDR, CYP27B1, and CYP24A1 genes and serum vitamin D levels as surrogate markers of disease progression in patients with acid reflux, Barrett's esophagus (BE), or esophageal adenocarcinoma (EAC). METHODS: We analyzed blood and tissue samples from patients with biopsy-confirmed BE or EAC for vitamin D levels, gene expressions, and polymorphisms in VDR (FokI [F/f], BsmI [B/b], ApaI [A/a], and TaqI [T/t]), CYP27B1 (HinfI [H/h]), and CYP24A1 (Hpy1881 [Y/y]). Percentages of homozygous dominant/recessive or heterozygous traits were assessed for each polymorphism in all patient subgroups. RESULTS: Genomic Bb and FF polymorphisms were highly prevalent in EAC patients, whereas BE patients had a high prevalence of wild-type Hpy1881 (YY polymorphism). Some polymorphisms (Yy for CYP24A1, bb for VDR) were noted only in EAC patients. Yy and bb forms were both uniquely present in some EAC patients without associated Barrett's lesions, but not in patients with concomitant BE. AA and bb polymorphisms were associated with decreased response to neoadjuvant therapy. A high level of VDR and CYP24A1 mRNA expression was observed in EAC tissue of non-responders. Serum vitamin D deficiency was common in EAC patients. CONCLUSIONS: Specific polymorphisms in vitamin D metabolism-related genes are associated with the likelihood of reflux-BE-EAC progression. Identifying such polymorphisms may aid in development of better surveillance and diagnostic and therapeutic protocols.