Metallothionein 2A core promoter region genetic polymorphism and its impact on the risk, tumor behavior, and recurrences of sinonasal inverted papilloma (Schneiderian papilloma)

Abstract

Inverted papillomas are a unique group of locally aggressive benign epithelial neoplasms in the nasal cavity and paranasal sinuses arising from the Schneiderian mucosa. Metallothioneins are sulfhydryl-rich heavy metal-binding proteins required for metal toxicity protection and regulation of biological mechanisms including proliferation and invasion. The goal of this study was to identify three SNPs at loci −5 A/G (rs28366003) and −209 A/G (rs1610216) in the core promoter region and at locus +838 C/G (rs10636) in 3′UTR region of the MT2A gene with IP risk and with tumor invasiveness according to Krouse staging. Genotyping was performed using the PCR restriction fragment length polymorphism technique in 130 genetically unrelated IP individuals, and 418 randomly selected healthy volunteers. The presence of the rs28366003 SNP was significantly related to the risk of IP within the present population-based case-control study. Compared to homozygous common allele carriers, heterozygosity and homozygosity for the G variant had a significantly increased risk of IP (adjusted odds ratio [OR] = 7.71, 95 % confidence interval [CI]: 4.01–14.91, p dominant < 0.001). Moreover, risk allele carriers demonstrated higher Krouse stage (pT1 vs. pT2-4) (OR = 19.32; 95 % CI, 2.30–173.53; p < 0.0001), diffuse tumor growth (OR = 4.58; 95 % CI, 1.70–12.11; p = 0.0008), bone destruction (OR = 4.13; 95 % CI, 1.50–11.60; p = 0.003), and higher incidence of tumor recurrences (OR = 5.11; 95 % CI, 1.68–15.20; p = 0.001). The findings suggest that MT2A gene variation rs28366003 may be implicated in the etiology of sinonasal inverted papilloma in a Polish population.

Zinc gluconate toxicity in wild-type vs. MT1/2-deficient mice

“…The association of single nucleotide polymorphisms (SNPs) at loci -5 A/G (rs28366003) and -209 A/G (rs1610216), as well as +838 C/G (rs10636) in the 3′ untranslated region of the MT2 gene were investigated in sinonasal inverted papillomas, which are locally aggressive benign epithelial neoplasms in the cavity and paranasal sinuses (Starska et al, 2015a). MT2 mRNA expression and Cd and Cu concentrations were negatively correlated with the -5 A/G SNP (Starska et al, 2015b).…”

Malignant transformation of sinonasal inverted papilloma and related genetic alterations: a systematic review

“…Starska et al [47], provides evidence for implicating MT2A polymorphisms in the development of SNIP. The findings also illustrate the key role played by the MT2A gene in inducing an aggressive Schneiderian papilloma phenotype.…”

“…The transcription of the MT gene (changes in the MT2A gene) is activated in response to a wide range of stimuli, including oxidative stress inducing agents, cytokines, hormones and various chemical agents [47]. Starska et al [47], provides evidence for implicating MT2A polymorphisms in the development of SNIP.…”

Mammalian Metallothionein-2A and Oxidative Stress

“…In recent years, ROS have generally been described as second messengers because of cellular signaling cascades and pathophysiological processes, such as proliferation, gene expression, adhesion, differentiation, senescence, apoptosis and necrosis [ 20 , 21 ], which are mediated by activated MAPKs [ 22 , 23 , 24 , 25 ]. Massive studies have revealed that oxidative stress played an important role in the pathogenesis of various diseases, such as coronary heart diseases (CHDs) [ 26 , 27 , 28 ], neurodegenerative disorders [ 29 , 30 ], cancer [ 31 , 32 , 33 ], and aging [ 34 , 35 ]. Overall, more evidences have indicated that MT2A, as a free radical scavenger, might protect cells and tissues from oxidative stress.…”