Genetic polymorphism of metallothionein 2A and risk of laryngeal cancer in a Polish population
- 273 Downloads
Metallothioneins are intracellular regulators of many biological mechanisms including differentiation, proliferation, angiogenesis and invasion, which are crucial processes in carcinogenesis. This study examines the association between three single-nucleotide polymorphisms 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 metallothionein 2A (MT2A) gene with squamous cell laryngeal cancer (SCLC) risk, as well as with tumor invasiveness according to tumor front grading (TFG). Genotyping was performed using the polymerase chain reaction–restriction fragment length polymorphism technique in 323 genetically unrelated individuals with SCLC and 418 randomly selected healthy volunteers. Only one SNP (rs28366003) was significantly related to laryngeal cancer in the study population. Compared with homozygous common allele carriers, heterozygous and homozygous for the G variant had significantly increased risk of SCLC [adjusted odds ratio (OR) = 2.90, 95 % confidence interval (CI) 1.53–5.21, p dominant < 0.001]. The A/G allele carriers at rs28366003 MT2A were at higher risk of SCLC development (OR = 2.63, 95 % CI 1.41–2.85, p < 0.001]. There was a significant association between the rs28366003 and stage and TFG classification. Most carriers of minor allele had a higher stage (OR = 2.76, 95 % CI 1.11–7.52, p = 0.03), increased cancer aggressiveness, as defined by a higher total TFG score (>18 points) (OR = 3.76, 95 % CI 1.15–12.56, p = 0.03) and diffuse tumor growth (OR = 5.86, 95 % Cl 0.72–44.79, p = 0.08). The results of this study raise a possibility that a genetic variation of MT2A may be implicated in the etiology of laryngeal cancer in a Polish population.
KeywordsMetallothionein 2A (MT2A) Single-nucleotide polymorphism (SNP) Tumor front grading (TFG) Laryngeal cancer
This work was supported, in part, by grant from the National Science Council, Poland (N403 043 32/2326) and by the statutory fund of the Department of Cytobiochemistry, University of Łódź, Poland (506/811).
Conflict of interest statement
The authors declare to have no conflict of interests.
The investigations were performed with the approval of the Bioethical Commission of the Medical University of Łódź and the National Science Council, Poland (approval no. RNN/60/13/KE).
- 7.Pan Y, Huang J, Xing R, Yin X, Cui J, Li W, Yu J, Lu Y. Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection. J Transl Med. 2013;11:173. doi: 10.1186/1479-5876-11-173.PubMedCentralPubMedCrossRefGoogle Scholar
- 8.Gumulec J, Balvan J, Sztalmachova M, Raudenska M, Dvorakova V, Knopfova L, Polanska H, Hudcova K, Ruttkay-Nedecky B, Babula P, Adam V, Kizek R, Stiborova M, Masarik M. Cisplatin-resistant prostate cancer model: differences in antioxidant system, apoptosis and cell cycle. Int J Oncol. 2014;44(3):923–33.PubMedGoogle Scholar
- 10.Habel N, Hamidouche Z, Girault I, Patiño-García A, Lecanda F, Marie PJ, Fromigué O. Zinc chelation: a metallothionein 2A’s mechanism of action involved in osteosarcoma cell death and chemotherapy resistance. Cell Death Dis. 2013;4:e874. doi: 10.1038/cddis.2013.405.PubMedCentralPubMedCrossRefGoogle Scholar
- 11.Kobierzycki C, Pula B, Skiba M, Jablonska K, Latkowski K, Zabel M, Nowak-Markwitz E, Spaczynski M, Kedzia W, Podhorska-Okolow M, Dziegiel P. Comparison of minichromosome maintenance proteins (MCM-3, MCM-7) and metallothioneins (MT-I/II, MT-III) expression in relation to clinicopathological data in ovarian cancer. Anticancer Res. 2013;33(12):5375–83.PubMedGoogle Scholar
- 19.Brazão-Silva MT, Cardoso SV, de Faria PR, Dias FL, Lima RA, Eisenberg AL, Nascimento MF, Loyola AM. Adenoid cystic carcinoma of the salivary gland: a clinicopathological study of 49 cases and of metallothionein expression with regard to tumour behaviour. Histopathology. 2013;63(6):802–9.PubMedCrossRefGoogle Scholar
- 20.Theocharis S, Klijanienko J, Giaginis C, Rodriguez J, Jouffroy T, Girod A, Point D, Tsourouflis G, Sastre-Garau X. Metallothionein expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patient survival. Histopathology. 2011;59:514–25.PubMedCrossRefGoogle Scholar
- 29.Seibold P, Hall P, Schoof N, Nevanlinna H, Heikkinen T, Benner A, Liu J, Schmezer P, Popanda O, Flesch-Janys D, Chang-Claude J. Polymorphisms in oxidative stress-related genes and mortality in breast cancer patients-potential differential effects by radiotherapy? Breast. 2013;22(5):817–23.PubMedCrossRefGoogle Scholar
- 32.Kanda M, Nomoto S, Okamura Y, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, Nakao A. Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis. Int J Oncol. 2009;35(3):477–83.PubMedGoogle Scholar
- 33.Tekin D, Kayaaltı Z, Söylemezoğlu T. The effects of metallothionein 2A polymorphism on lead metabolism: are pregnant women with a heterozygote genotype for metallothionein 2A polymorphism and their newborns at risk of having higher blood lead levels? Int Arch Occup Environ Health. 2012;85(6):631–7.PubMedCrossRefGoogle Scholar
- 35.Dutsch-Wicherek M, Popiela TJ, Klimek M, Rudnicka-Sosin L, Wicherek L, Oudinet JP, Skladzien J, Tomaszewska R. Metallothionein stroma reaction in tumor adjacent healthy tissue in head and neck squamous cell carcinoma and breast adenocarcinoma. Neuro Endocrinol Lett. 2005;26:567–74.PubMedGoogle Scholar