Immunohistochemical evaluation of vitamin D receptor (VDR) expression in cutaneous melanoma tissues and four VDR gene polymorphisms

Abstract

Objective: : Vitamin D receptor (VDR) mediates vitamin D activity. We examined whether VDR expression in excised melanoma tissues is associated with VDR gene (VDR) polymorphisms.

Methods: : We evaluated VDR protein expression (by monoclonal antibody immunostaining), melanoma characteristics, and carriage of VDR-FokI-rs2228570 (C>T),VDR-BsmI-rs1544410 (G>A),VDR-ApaI-rs7975232 (T>G), andVDR-TaqI-rs731236 (T>C) polymorphisms (by restriction fragment length polymorphism). Absence or presence of restriction site was denoted by a capital or lower letter, respectively: " F" and " f" for FokI, " B" and " b" for BsmI, " A" and " a" for ApaI, and " T" and " t" for TaqI endonuclease. Seventy-four Italian cutaneous primary melanomas (52.1±12.7 years old) were studied; 51.4% were stage I, 21.6% stage II, 13.5% stage III, and 13.5% stage IV melanomas. VDR expression was categorized as follows: 100% positivevs. <100%; over the median 20% (high VDR expression) vs. ≤20% (low VDR expression); absence vs. presence of VDR-expressing cells.

Results: : Stage I melanomas, Breslow thickness of <1.00 mm, level II Clark invasion, Aa heterozygous genotype, and AaTT combined genotype were more frequent in melanomas with high vs. low VDR expression. Combined genotypes BbAA, bbAa, AATt, BbAATt, and bbAaTT were more frequent in 100% vs. <100% VDR-expressing cells. Combined genotype AATT was more frequent in melanomas lacking VDR expression (odds ratio=14.5; P=0.025). VDR expression was not associated with metastasis, ulceration, mitosis >1, regression, tumor-infiltrating lymphocytes, tumoral infiltration of vascular tissues, additional skin and non-skin cancers, and melanoma familiarity.

Conclusions: : We highlighted that VDR polymorphisms can affect VDR expression in excised melanoma cells. Low VDR expression in AATT carriers is a new finding that merits further study. VDR expression possibly poses implications for vitamin D supplementation against melanoma. VDR expression and VDR genotype may become precise medicinal tools for melanoma in the future.

Keywords: FokI polymorphism; VDR polymorphism; VDR protein expression; Vitamin D receptor; cutaneous melanoma; metastatic melanoma; predictive biomarkers; skin cancer.

1

Representative image of VDR protein expression in cutaneous melanoma tissue. Melanoma showing diffuse positivity for VDR expression. Eroded epidermis (H&E staining, 25×. Bar indicates 50 μm).

2

Representative image of VDR protein expression in cutaneous melanoma tissue. Melanoma featuring tumor-infiltrating lymphocytes (TILs). Intraepidermal component of lesion (at the bottom of image) shows strong positivity for VDR expression (H&E staining, 25×. Bar indicates 50 μm).

3

Representative image of VDR protein expression in cutaneous melanoma tissue. Melanoma featuring TILs. In this case, melanoma cells nesting in the dermis are negative throughout the whole lesion (H&E staining, 25×. Bar indicates 50 μm).