Interleukin 1 receptor antagonist gene variable number of tandem repeats polymorphism and cutaneous melanoma

Cauci,Sabina; Buligan,Cinzia; Rocchi,Francesco; Salvador,Ilaria; Xodo,Luigi; Stinco,Giuseppe

doi:10.3892/ol.2019.10923

Interleukin 1 receptor antagonist gene variable number of tandem repeats polymorphism and cutaneous melanoma

Authors:
- Sabina Cauci
- Cinzia Buligan
- Francesco Rocchi
- Ilaria Salvador
- Luigi Xodo
- Giuseppe Stinco
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Affiliations: Department of Medicine, University of Udine, I‑33100 Udine, Italy
Published online on: September 25, 2019 https://doi.org/10.3892/ol.2019.10923
Pages: 5759-5768
Copyright: © Cauci et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Immunity and cytokines serve crucial roles in cutaneous melanoma. The present study investigated whether a variable number tandem repeat (VNTR) polymorphism of interleukin‑1 receptor antagonist (IL‑1RA) gene (IL‑1RN) located in intron 2 (rs2234663) is associated with cutaneous melanoma. A total of 515 subjects were studied, 133 of which were cutaneous melanoma cases (72 stage I+II non‑metastatic melanoma cases and 61 stage III+IV metastatic melanoma cases), and 382 subjects were matching healthy controls from the Friuli‑Venezia‑Giulia Region located in Northeast Italy, an area with a high melanoma incidence. The IL‑1RN‑VNTR polymorphism was determined by DNA fragment length analysis following PCR amplification. According to the number of 86‑bp repeats, five different IL‑1RN alleles were identified: Allele 1 (4‑repeats), allele 2 (2‑repeats, short allele), allele 3 (5‑repeats), allele 4 (3‑repeats) and allele 5 (6‑repeats). Alleles with three or more 86‑bp repeats, i.e. allele 1, 3, 4 and 5 were collectively denoted as long (L) repeats. The present study revealed that IL‑1RN‑VNTR 1/2 and 2/L genotypes were more frequent among patients with cutaneous melanoma (43.6 and 45.1%, respectively) compared with healthy controls [29.6 and 30.6%, respectively; odds ratio (OR), 1.84; CI, 1.22‑2.77; P=0.003; and OR, 1.66; CI, 1.24‑2.79; P=0.002, respectively]. Conversely, the IL‑1RN‑VNTR 1/1 genotype was less frequent among melanoma cases (45.9%) compared with healthy controls (57.9%; OR, 0.62; CI, 0.41‑0.92; P=0.017). Comparison of metastatic vs. non‑metastatic melanoma cases identified no significant differences. The present study first demonstrated that carriage of the 1/1 IL‑1RN‑VNTR genotype was protective, whereas 1/2 and 2/L was a risk factor for patients with cutaneous melanoma vs. healthy controls. The short allele 2 was associated with higher expression levels of IL‑1RA, a potent competitive inhibitor of the proinflammatory cytokines IL‑1α and IL‑1β. VNTR‑IL‑1RN polymorphism may affect susceptibility to melanoma and, thus, it is a potential novel diagnostic biomarker for melanoma. The present study increased the understanding of genetic melanoma susceptibility/carcinogenesis, and may indicate novel strategies in the personalized prevention of cutaneous melanoma.

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