The role of MGMT polymorphisms (Rs12917 and Rs11016879) in head and neck cancer risk and prognosis

  • Paweł Kiczmer Department of medical and molecular Biology, Medical University of Silesia, Zabrze, Poland
  • Alicja Prawdzic Seńkowska Department of medical and molecular Biology, Medical University of Silesia, Zabrze, Poland
  • Joanna Katarzyna Strzelczyk Department of medical and molecular Biology, Medical University of Silesia, Zabrze, Poland
  • Błażej Szydło Department of medical and molecular Biology, Medical University of Silesia, Zabrze, Poland
  • Krzysztof Biernacki Department of medical and molecular Biology, Medical University of Silesia, Zabrze, Poland
  • Tadeusz Osadnik 1 2nd Department of Cardiology and Angiology, Silesian Center for Heart Disease, Zabrze, Poland; 2 Genomics Laboratory, Kardio-Med Silesia Science and Technology Park, Zabrze, Poland;
  • Łukasz Krakowczyk Department of Oncological and Reconstructive Surgery, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland;
  • Zofia Ostrowska Department of medical and molecular Biology, Medical University of Silesia, Zabrze, Poland

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the leading cancers by incidence worldwide. The risk of these cancers is strictly associated with alkylation factors present in tobacco smoke. The crucial role in preventing DNA alkylation is played by O6-methylguanine-DNA methyltransferase (MGMT). Dysfunction or lack of MGMT is associated with an increased risk of cancer. The aim of the study was to assess the influence of MGMT polymorphisms: Rs12917 and Rs11016879 on HNSCC risk and course. The study consisted of 42 HNSCC patients and 58 healthy individuals. Case samples were taken from resected tumour tissue. The control group comprised samples of epithelial cells collected from mucous membranes using swabs. To analyse the SNPs we performed Real-Time PCR. DNA samples were genotyped by employing the 5' nuclease assay for allelic discrimination using TaqMan SNP Genotyping Assays. The significance between distributions of genotypes and alleles was tested using the Pearson’s χ2 test analysis. The MGMT Rs12917 TT genotype was observed only in the HNSCC patients. In case of Rs11016879 no increase in the risk was observed (p>0.05). However, we noted higher risk of nodal metastasis in Rs11016879 homozygotes [OR=10.67 (95% CI=0.36-23.93), p=0.03]. Our findings suggest that MGMT gene polymorphisms may play an important role in risk and prognosis of HNSCC. Mechanisms leading to MGMT enzymatic defect remain unknown and hence further studies need to be carried out into this topic.

References

Bartkowski, S B. (1996) Chirurgia szczękowo-twarzowa. Ages, Kraków 33-34

Burusapat C, Jarungroongruangchai W, Charoenpitakchai M (2015) Prognostic factors of cervical node status in head and neck squamous cell carcinoma. World J Surg Oncol 13: 51 https://doi.org/10.1186/s12957-015-0460-6

Czech A, Fedyunin I, Zhang G and Ignatova Z (2010) Silent mutations in sight: Co-variations in tRNA abundance as a key to unravel consequences of silent mutations. Molecular bioSyst 6(10): 1767–1772

Doecke, J, Zhao, Z Z, Pandeya, N, Sadeghi, S, Stark, M, Green, A C,

Hayward, N K, Webb, P M and Whiteman, D C. (2008) Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma. Int J Cancer 123: 174–180. http://dx.doi.org/10.1002/ijc.23410

Du, L, Wang, H, Xiong, T, Ma, Y, Yang, J, Huang, J, Zeng, D, Wang, X and Huang, H. (2013) The polymorphisms in the MGMT gene and the risk of cancer. A meta-analysis. Tumour biol 34: 3227–3237. http://dx.doi.org/10.1007/s13277-013-0893-x

Egyhazi, S, Ma, S, Smoczynski, K, Hansson, J, Platz, A and Ringborg, U. (2002) Novel O6-methylguanine-DNA methyltransferase SNPs: a frequency comparison of patients with familial melanoma and healthy individuals in Sweden. Hum mutat 20: 408–409. http://dx.doi.org/10.1002/humu.9078

Fogli, A, Chautard, E, Vaurs-Barriere, C, Pereira, B, Muller-Barthelemy, M,

Court, F, Biau, J, Pinto, A A, Kemeny, J-L, Khalil, T, Karayan-Tapon, L, Verrelle, P, Costa, B M and Arnaud, P. (2016) The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients' survival. Carcinogenesis 37: 169–176. http://dx.doi.org/10.1093/carcin/bgv251

Hall, J, Hashibe, M, Boffetta, P, Gaborieau, V, Moullan, N, Chabrier, A, Zaridze, D, Shangina, O, Szeszenia-Dabrowska, N, Mates, D, Janout, V, Fabianova, E, Holcatova, I, Hung, R J, McKay, J, Canzian, F and Brennan, P. (2007) The association of sequence variants in DNA repair and cell cycle genes with cancers of the upper aerodigestive tract. Carcinogenesis 28: 665–671. http://dx.doi.org/10.1093/carcin/bgl160

Hashibe, M, Brennan, P, Chuang, S-C, Boccia, S, Castellsague, X, Chen, C, Curado, M P, Dal Maso, L, Daudt, A W, Fabianova, E, Fernandez, L, Wunsch-Filho, V, Franceschi, S, Hayes, R B, Herrero, R, Kelsey, K, Koifman, S, La Vecchia, C, Lazarus, P, Levi, F, Lence, J J, Mates, D, Matos, E, Menezes, A, McClean, M D, Muscat, J, Eluf-Neto, J, Olshan, A F, Purdue, M, Rudnai, P, Schwartz, S M, Smith, E, Sturgis, E M, Szeszenia-Dabrowska, N, Talamini, R, Wei, Q, Winn, D M, Shangina, O, Pilarska, A, Zhang, Z-F, Ferro, G, Berthiller, J and Boffetta, P. (2009) Interaction between tobacco and alcohol use and the risk of head and neck cancer. Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer epidemiology, biomarkers prev 18: 541–550. http://dx.doi.org/10.1158/1055-9965.EPI-08-0347

Huang W-Y, Olshan A F, Schwartz S M, Berndt S I, Chen C, Llaca V, Chanock S J, Fraumeni J F, JR and Hayes R B (2005) Selected genetic polymorphisms in MGMT, XRCC1, XPD, and XRCC3 and risk of head and neck cancer: A pooled analysis. Cancer Epidemiol Biomarkers Prev 14(7): 1747–1753 http://dx.doi.org/10.1158/1055-9965.EPI-05-0162

Jacob R, Shafiei N, Nagel G, Welkoborsky H J, Mann W and Kaina B (2010) MGMT activity in mucosal epithelium and squamous cell carcinoma of the head and neck. Anticancer res 30(7): 2561–2566

Kimchi-Sarfaty, C, Oh, J M, Kim, I-W, Sauna, Z E, Calcagno, A M, Ambudkar, S V and Gottesman, M M. (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315: 525–528. http://dx.doi.org/10.1126/science.1135308

Komar, A A, Lesnik, T and Reiss, C. (1999) Synonymous codon substitutions affect ribosome traffic and protein folding during in vitro translation. FEBS Letters 462: 387–391. http://dx.doi.org/10.1016/S0014-5793(99)01566-5

Kordek, R, Jassem, J, Jeziorski, A, Kornafel, J, Krzakowski, M and Pawlęga, J. (2013) Onkologia. Podręcznik dla studentów. Via Medica, Gdańsk, 2013. 146-157

Kreimer, A R, Clifford, G M, Boyle, P and Franceschi, S. (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14: 467–475. http://dx.doi.org/10.1158/1055-9965.EPI-04-0551

Krzakowski, M and Warzocha, K. (2013) .). Nowotwory nabłonkowe narządów głowy i szyi. In: Zalecenia postępowania diagnostyczno-terapeutycznego w nowotworach złośliwych. 2013 Via Medica, Gdańsk 5-13

Lee Moore, Brennan, P, Karami, S, Menashe, I, Berndt, S I, Dong, L M, Meisner, A, Yeager, M, Chanock, S, Colt, J, Schwartz, K, Davis, F, Zaridze, D, Mattveev, V, Janout, V,Kollarova, H, Bencko, V, Navratilova, M, Szeszenia-Dabrowska, N, Mates, D, Holcatova, I, Boffetta, P, Chow, W H, Rosenberg, P S and Rothman, N. (2009) Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk. Cancer res 69: 8001–8008 suppl 1 http://dx.doi.org/10.1158/0008-5472.CAN-09-1734

Leemans, C. R., Tiwari, R., Nauta, J. J. P., Waal, I. V. D. and Snow, G. B. (1994), Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Cancer, 73: 187–190. doi:10.1002/1097-0142(19940101)73:1<187::AID-CNCR2820730132>3.0.CO;2-J

Ma, W-J, Lv, G-D, Zheng, S-T, Huang, C-G, Liu, Q, Wang, X, Lin, R-Y, Sheyhidin, I and Lu, X-M (2010) DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang, China. World j gastroenterol 16: 641–647.

Maier H, Dietz A, Gewelke U, Heller W D and Weidauer H (1992) Tobacco and alcohol and the risk of head and neck cancer. Clin investig 70(3-4): 320–327

Majchrzak, E, Szybiak, B, Wegner, A, Pienkowski, P, Pazdrowski, J, Luczewski, L, Sowka, M, Golusinski, P, Malicki, J and Golusinski, W (2014) Oral cavity and oropharyngeal squamous cell carcinoma in young adults: a review of the literature. Radiol Oncol 48: 1–10. http://dx.doi.org/10.2478/raon-2013-0057

Marur, S and Forastiere, A A. (2008) Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clinic proc 83: 489–501. http://dx.doi.org/10.4065/83.4.489

Molina, E, Perez-Morales, R, Rubio, J, Petrosyan, P, Cadena, L H, Arlt, V M, Phillips, D H and Gonsebatt, M E. (2013) The GSTM1null (deletion) and MGMT84 rs12917 (Phe/Phe) haplotype are associated with bulky DNA adduct levels in human leukocytes. Mutat res 758: 62–68. http://dx.doi.org/10.1016/j.mrgentox.2013.09.007

Ndiaye, C, Mena, M, Alemany, L, Arbyn, M, Castellsagué, X, Laporte, L, Bosch, F X, Sanjosé, S de and Trottier, H (2014) HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers. A systematic review and meta-analysis. The Lancet Oncology 15: 1319–1331. http://dx.doi.org/10.1016/S1470-2045(14)70471-1

Onerci Celebi O., Tezel GG., Hosal AS, Cenquiz M, Gullu IH, Hayran M (2016) Detection of O6-methylguanine-DNA methyltransferase gene promoter region methylation pattern using pyrosequencing and the effect of methylation pattern on survival, recurrence, and chemotherapy sensitivity in patients with laryngeal cancer. Pathol Res Pract 212: 456–62. https://doi.org/10.1016/j.prp.2016.02.022

Pfeifer G P, Denissenko M F, Olivier M, Tretyakova N, Hecht S S and Hainaut P (2002) Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21(48): 7451 http://dx.doi.org/10.1038/sj.onc.1205803

Qiu Z X, Xue F, Shi X F, He X, Ma H N, Chen L, Chen P Z (2014) MGMT Leu84Phe gene polymorphism and lung cancer: a meta analysis. Tumor biol 35: 4381-4387 https://doi.org/10.1007/s13277-013-1576-3

Ragin, C C R, Modugno, F and Gollin, S M (2007) The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res 86: 104–114.

Rapkins R W, Wang F, Nguyen H N, Cloughesy T F, Lai A, Ha W, Nowak A K, Hitchins M P and McDonald K L (2015) The MGMT promoter SNP rs16906252 is a risk factor for MGMT methylation in glioblastoma and is predictive of response to temozolomide. Neuro oncol 17(12): 1589–1598 http://dx.doi.org/10.1093/neuonc/nov064

Sawhney, M, Rohatgi, N, Kaur, J, Gupta, S D, Deo, S V, Shukla, N K and Ralhan, R (2012) MGMT expression in oral precancerous and cancerous lesions. Correlation with progression, nodal metastasis and poor prognosis. Oral Oncology 43: 515–522. http://dx.doi.org/10.1016/j.oraloncology.2006.05.007

Sharma, S, Salehi, F, Scheithauer, B W, Rotondo, F, Syro, L V and Kovacs, K (2009) Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer res 29: 3759–3768. http://dx.doi.org/

Shen, L X, Basilion, J P and Stanton, V P, JR (1999) Single-nucleotide polymorphisms can cause different structural folds of mRNA. Proc Natl Acad Sci U S A 96: 7871–7876. http://dx.doi.org/

Strzelczyk J K, Golabek K, Krakowczyk L and Owczarek A J (2016) Expression profiles of MGMT, p16, and APC genes in tumor and matching surgical margin from patients with oral squamous cell carcinoma. Acta biochi Pol 63(3): 505–509 http://dx.doi.org/10.18388/abp.2015_1204

Wibom, C, Sjostrom, S, Henriksson, R, Brannstrom, T, Broholm, H, Ryden, P, Johansen, C, Collatz-Laier, H, Hepworth, S, McKinney, P A, Bethke, L, Houlston, R S, Andersson, U and Melin, B S (2012) DNA-repair gene variants are associated with glioblastoma survival. Acta oncol 51: 325–332. http://dx.doi.org/10.3109/0284186X.2011.616284

Yu, D, Cao, T, Han, Y-D and Huang, F-S (2016) Relationships between MGMT promoter methylation and gastric cancer. A meta-analysis. OncoTargets and therapy 9: 6049–6057. http://dx.doi.org/10.2147/OTT.S114052

Zhang, Z, Wang, L, Wei, S, Liu, Z, Wang, L E, Sturgis, E. M., & Wei, Q. (2010) Polymorphisms of the DNA repair gene MGMT and risk and progression of head and neck cancer. DNA repair, 9(5): 558-566. https://dx.doi.org/10.1016%2Fj.dnarep.2010.02.006

Zhong Y, Huang Y, Huang Y, Zhang T, Ma C, Zhang S, Fan W, Chen H, Quian J, Lu D (2010) Effects of O6-methylguanine-DNA methyltransferase (MGMT) polymorphisms on cancer: a meta-analysis. Mutagenesis 25: 83–95. https://doi.org/10.1093/mutage/gep050

Ziółkowska, E, Biedka M, Windorbska, W, (2011) Odczyn popromienny u chorych na raka region głowy I szyi: mechanizmy I konsekwencje. Otolaryngologia 10(4): 147 - 153

Published
2018-05-27
Section
Articles