BsmI (rs1544410) and FokI (rs2228570) vitamin D receptor polymorphisms, smoking, and body mass index as risk factors of cutaneous malignant melanoma in northeast Italy

Abstract

Objective: To investigate whether vitamin D receptor gene (VDR) BsmI-rs1544410 and FokI-rs2228570 polymorphisms, smoking duration, and body mass index (BMI) are risk factors for cutaneous melanoma, especially metastatic melanoma. Methods: We studied 120 cutaneous melanoma cases [68 stage I and II non-metastatic melanoma (NMetM) patients, plus 52 Stage III and IV metastatic melanoma (MetM) patients], and 120 matching healthy controls from northeast Italy. VDR polymorphisms were measured by restriction fragment length polymorphism analysis. Absence or presence of BsmI and FokI restriction sites was denoted by " B” and " F” or by " b” and " f,” respectively. Results: VDR-BsmI bb genotype was more frequent among MetM (32.7%) than among NMetM cases (13.2%), with odds ratio (OR)=3.18. Comparison of all melanoma patients vs healthy controls showed that the following biomarkers were at risk: ≥20 years of smoking (OR=2.43); ≥20 years of smoking combined with bb (OR=4.78), Bb+bb (OR=2.30), Ff (OR=3.04), and Ff+ff (OR=3.08); obesity (BMI>30 kg/m2) alone (OR=3.54); and obesity combined with Bb+bb (OR=3.52), Ff (OR=4.78), and Ff+ff (OR=6.56). Comparison of MetM vs NMetM patients revealed that the following biomarkers were at risk: ≥20 years of smoking (OR=2.39), ≥20 years of smoking combined with bb (OR=5.13), Bb+bb (OR=3.07), and Ff+ff (OR=2.66); and obesity combined with Bb+bb (OR=5.27), Ff (OR=6.28), and Ff+ff (OR=9.18). Triple combination of ≥20 years of smoking, obesity, and Bb+bb yielded OR=9.65 for melanoma patients vs healthy controls and OR=12.2 for MetM vs. NMetM patients. Conclusions: Risk factors for cutaneous MetM include two VDR polymorphisms combined with smoking duration and obesity. Results suggest gene-environment implications in melanoma susceptibility and severity. Future studies in larger cohorts and in subjects with different genetic background are warranted to extend our findings.

25-Hydroxyvitamin D status, vitamin D intake, and skin cancer risk: a systematic review and dose–response meta-analysis of prospective studies

“…Another hypothesis to explain the positive association between vitamin D status and skin cancer risk may be attributed to genetic factors. Several studies have addressed the issue of whether single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene are associated with the risk of developing different types of cancer 82 , 83 , and several VDR variants have been investigated in relation to skin cancer risk 84 , 85 , with three meta-analyses supporting a positive association, particularly with FokI and BsmI 86 – 88 . Since vitamin D exerts a function of engagement of its receptor VDR, it is likely that some SNPs of the VDR gene affect the ability of interacting with its ligand, which ultimately would lead to different levels of the biologic activity of vitamin D and increase skin cancer risk.…”

Antiproliferative Activity of Non-Calcemic Vitamin D Analogs on Human Melanoma Lines in Relation to VDR and PDIA3 Receptors

“…Of note is that its decreased expression correlates with advanced melanoma staging, progression and decreased overall patient survival and disease-free survival time [ 45 , 46 ]. Accordingly, VDR polymorphism [ 41 , 42 , 72 ] and decreased levels of 25(OH)D 3 in the serum [ 33 , 86 ] positively correlate with melanoma prevalence and poor prognosis.…”

“…The anti-melanoma activity of vitamin D derivatives have been reported previously [ 35 , 36 , 37 , 38 , 39 , 40 ]. In addition, the presence of specific polymorphisms of VDR [ 41 , 42 , 43 ] or a decreased expression of VDR , CYP27B1 , CYP24A1 and defects in vitamin D signaling are linked to more advanced stages of melanoma or poorer prognosis [ 44 , 45 , 46 , 47 , 48 ]. Furthermore, proper supplementation with vitamin D is believed to be an important factor in cancer prevention [ 47 , 49 , 50 , 51 ].…”

Sun Exposure and Melanoma, Certainties and Weaknesses of the Present Knowledge

“…Vitamin D and its receptor polymorphisms might play an important role as risk factors for CMM ( 70 ). It is very well known that UV radiation is essential for Vitamin D synthesis, in particular for the photoconversion of 7-dehydrocholesterol to cholecalciferol in the epidermis.…”