Biomedical papers - Ahead of Print

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. X:X | 10.5507/bp.2018.012

Elevated DNA methylation in malignant tumors of the sinonasal tract and its association with patient survival

Marcela Chmelarovaa, Jan Lacob, Helena Kovarikovaa, Ivana Baranovaa, Pavel Dundrc, Kristyna Nemejcovac, Jaroslav Michalekd, Milan Vosmike, Vladimir Palickaa
a Institute for Clinical Biochemistry and Diagnostics, Charles University, Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Czech Republic
b The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Czech Republic
c Department of Pathology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic
d Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic
e Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Czech Republic

Background: Epigenetic modifications have been recognized as an important mechanism underlying carcinoma progression. DNA methylation plays an important role in cancer biology and represents potentially heritable changes in gene expression that do not involve DNA sequence. The aim of this study was to investigate promoter methylation of selected genes in sinonasal carcinoma by comparison with noncancerous sinonasal tissue.

Methods: To search for epigenetic events (methylation in 25 tumor suppressor genes) we used MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification) to compare methylation status of 59 formalin fixed, paraffin embedded tissue samples of sinonasal carcinomas with 18 control samples. The most important changes in methylation were confirmed using MSP (Methylation specific PCR). Detected alterations in methylation were compared with clinicopathological characteristics.

Results: Using a 20% cut-off for methylation (MS-MLPA), we found significantly higher methylation in GATA5 (P=0.0005), THSB1 (P=0.0002) and PAX5 (P=0.03) genes in the sinonasal cancer group compared to the control group. Methylation in five or more genes was associated with impaired overall survival (P=0.017).

Conclusion: These findings provide evidence that alterations in methylation profile may be one of the major mechanisms in sinonasal carcinogenesis. In addition, changes in methylation could potentially be used as prognostic factors of sinonasal carcinoma and may have implications for future individualized therapy based on epigenetic changes.

Keywords: biomarkers, DNA methylation, sinonasal carcinoma, epigenetics

Received: November 27, 2017; Accepted: March 21, 2018; Prepublished online: March 27, 2018


References

  1. Haerle SK, Gullane PJ, Witterick IJ, Zweifel C, Gentili F. Sinonasal carcinomas: epidemiology, pathology, and management. Neurosurg Clin N Am 2013;24(1):39-49. Go to original source... Go to PubMed...
  2. www.svod.cz
  3. Turner JH, Reh DD. Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck 2012;34(6):877-85. Go to original source... Go to PubMed...
  4. Syrjänen K, Syrjänen S. Detection of human papillomavirus in sinonasal carcinoma: systematic review and meta-analysis. Hum Pathol 2013;44(6):983-91. Go to original source... Go to PubMed...
  5. Llorente JL, López F, Suárez C,Hermsen MA. Sinonasal carcinoma: clinical, pathological, genetic and therapeutic advances. Nat Rev Clin Oncol 2014;11(8):460-72. Go to original source... Go to PubMed...
  6. López F, Llorente JL, Costales M, García-Inclán C, Pérez-Escuredo J, Alvarez-Marcos C, Hermsen M, Suárez C. Molecular characterisation of sinonasal carcinomas and their clinical implications. Acta Otorrinolaringol Esp 2013;64(4):289-96. Go to original source... Go to PubMed...
  7. Laco J, Sieglová K, Voąmiková H, Dundr P, Němejcová K, Michálek J, Čelakovský P, Chrobok V, Mottl R, Mottlová A, Tuček L, Slezák R, Chmelařová M, Sirák I, Voąmik M, Ryąka A. The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis. Virchows Arch 2015;467(4):405-15. Go to original source... Go to PubMed...
  8. Chmelarova M, Sirak I, Mzik M, Sieglova K, Vosmikova H, Dundr P, Němejcová K, Michálek J, Voąmik M, Palička V, Laco J. Importance of tumor suppressor genes methylation in sinonasal carcinomas. Folia Biol (Praha) 2016;62(3):110-9. Go to PubMed...
  9. Laco J, Chmelařová M, Voąmiková H, Sieglová K, Bubancová I, Dundr P, Němejcová K, Michálek J, Čelakovský P, Mottl R, Sirák I, Voąmik M, Ryąka A. SMARCB1/INI1-deficient sinonasal carcinoma shows methylation of RASSF1 gene: A clinicopathological, immunohistochemical and molecular genetic study of a recently described entity. Pathol Res Pract 2017;213(2):133-42. Go to original source... Go to PubMed...
  10. Griffith JS, Mahler HR. DNA ticketing theory of memory. Nature 1969;223(5206):580-2. Go to original source... Go to PubMed...
  11. Curradi M, Izzo A, Badaracco G, Landsberger N. Molecular mechanisms of gene silencing mediated by DNA methylation. Mol Cell Biol 2002;22(9):3157-73. Go to original source... Go to PubMed...
  12. Chmelarova M, Krepinska E, Spacek J, Laco J, Mzik M, Palicka V. Promoter methylation of GATA4, WIF1, NTRK1 and other selected tumor suppressor genes in ovarian cancer. Folia Biol (Praha) 2013;59(2):87-92. Go to PubMed...
  13. Bubancova I, Kovarikova H, Laco J, Ruszova E, Dvorak O, Palicka V, Chmelarova M. Next-generation sequencing approach in methylation analysis of HNF1B and GATA4 genes: searching for biomarkers in ovarian cancer. Int J Mol Sci 2017;18(2):pii:E474. Go to original source... Go to PubMed...
  14. Rao-Bindal K, Kleinerman ES. Epigenetic regulation of apoptosis and cell cycle in osteosarcoma. Sarcoma 2011;679457. Go to original source... Go to PubMed...
  15. Barnes L, Eveson JW, Reichart P and Sidransky D, editors. Tumours of the Nasal Cavity and Paranasal Sinuses. Lyon: IARC Press; 2005.
  16. Nygren AO, Ameziane N, Duarte HM, Vijzelaar RN, Waisfisz Q, Hess CJ, Schouten JP, Errami A. Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res 2005;33(14):e128. Go to original source... Go to PubMed...
  17. Iaccarino C, Orlandi E, Ruggeri F, Nicoli D, Torricelli F, Maggi M, Cerasti D, Pisanello A, Pedrazzi G, Froio E, Crafa P, D'Abbiero N, Michiara M, Ghadirpour R, Servadei F. Prognostic value of MGMT promoter status in non-resectable glioblastoma after adjuvant therapy. Clin Neurol Neurosurg 2015;132:1-8. Go to original source... Go to PubMed...
  18. Paulíková S, Chmelařová M, Petera J, Palička V, Paulík A. Hypermethylation of RAD51L3 and XRCC2 genes to predict late toxicity in chemoradiotherapy-treated cervical cancer patients. Folia Biol (Praha) 2013;59(6):240-5. Go to PubMed...
  19. Sailer V, Holmes EE, Gevensleben H, Goltz D, Dröge F, Franzen A, Dietrich J, Kristiansen G, Bootz F, Schröck A, Dietrich D. PITX3 DNA methylation is an independent predictor of overall survival in patients with head and neck squamous cell carcinoma. Clin Epigenetics 2017;9:12. doi: 10.1186/s13148-017-0317-7. eCollection Go to original source... Go to PubMed...
  20. Shen Z, Zhou C, Li J, Ye D, Deng H, Cao B, Hao W, Lin L, Zhang Y. SHISA3 Promoter Methylation Is a Potential Diagnostic and Prognostic Biomarker for Laryngeal Squamous Cell Carcinoma. Biomed Res Int 2017;9058749. doi: 10.1155/2017/9058749 Go to original source... Go to PubMed...
  21. Chen X, Hu H, Liu J, Yang Y, Liu G Ying X1, Chen Y, Li B, Ye C, Wu D, Duan S. FOXF2 promoter methylation is associated with prognosis in esophageal squamous cell carcinoma. Tumour Biol 2017;39(2):1010428317692230.
  22. Mzik M, Chmelarova M, John S, Laco J, Slaby, O Kiss I, Bohovicová L, Palicka V, Nekvindova J. Aberrant methylation of tumour suppressor genes WT1, GATA5 and PAX5 in hepatocellular carcinoma. Clin Chem Lab Med 2016;54(12):1971-80. Go to original source... Go to PubMed...
  23. Zhang X, Song YF, Lu HN, Wang DP, Zhang XS Huang SL, Sun BL, Huang ZG. Combined detection of plasma GATA5 and SFRP2 methylation is a valid noninvasive biomarker for colorectal cancer and adenomas. World J Gastroenterol 2015;21(9):2629-37. Go to original source... Go to PubMed...
  24. Rankeillor KL, Cairns DA, Loughrey C, Short SC, Chumas P, Ismail A, Chakrabarty A, Lawler SE, Roberts P. Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma. J Neurooncol 2014;117(2):243-51. Go to original source... Go to PubMed...
  25. Chmelarova M, Krepinska E, Spacek J, Laco J, Nekvindova J, Palicka V. Methylation analysis of tumor suppressor genes in ovarian cancer using MS-MLPA. Folia Biol (Praha) 2012;58(6):246-50. Go to PubMed...
  26. Huang C, Zhou X, Li Z, Liu H, He Y, Ye G, Huang K. Downregulation of thrombospondin-1 by DNA hypermethylation is associated with tumor progression in laryngeal squamous cell carcinoma. Mol Med Rep 2016;14(3):2489-96. Go to original source... Go to PubMed...
  27. Shitani M, Sasaki S, Akutsu N, Takagi H, Suzuki H, Nojima M, Yamamoto H, Tokino T, Hirata K, Imai K, Toyota M, Shinomura Y. Genome-wide analysis of DNA methylation identifies novel cancer-related genes in hepatocellular carcinoma. Tumour Biol 2012;33(5):1307-17. Go to original source... Go to PubMed...
  28. Pesek M, Kopeckova M, Benesova L, Meszarosova A, Mukensnabl P, Bruha F, Minarik M. Clinical significance of hypermethylation status in NSCLC: evaluation of a 30-gene panel in patients with advanced disease. Anticancer Res 2011;31(12):4647-52. Go to PubMed...
  29. Ding N, Bonham EM, Hannon BE, Amick TR, Baylin SB, O'Hagan HM. Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage. J Mol Cell Biol 2016;8(3):244-54. Go to original source... Go to PubMed...
  30. Wang YJ, He L, Yuan M, Tsang WW, Hao L, Wang M, Chow LW, Cheung MN, Liu Q, Ng EL, Loo WT, Chow CY, Bai LJ, Yang Z. Epigenetic changes of TIMP-3, GSTP-1 and 14-3-3 sigma genes as indication of status of chronic inflammation and cancer. Int J Biol Markers 2014;29(3),e208-14. Go to original source... Go to PubMed...