International Journal of Head and Neck Surgery

Register      Login

VOLUME 1 , ISSUE 2 ( May-August, 2010 ) > List of Articles


Consistent DNA Hypermethylation Patterns in Laryngeal Papillomas

Josena K Stephen, Kang Mei Chen, Veena Shah, Vanessa G Schweitzer, Glendon Gardner, Michael S Benninger, Maria J Worsham

Citation Information : Stephen JK, Chen KM, Shah V, Schweitzer VG, Gardner G, Benninger MS, Worsham MJ. Consistent DNA Hypermethylation Patterns in Laryngeal Papillomas. Int J Head Neck Surg 2010; 1 (2):69-77.

DOI: 10.5005/jp-journals-10001-1013

Published Online: 01-12-2011

Copyright Statement:  Copyright © 2010; The Author(s).



This study examined the contribution of promoter hypermethylation to the pathogenesis of respiratory papillomatosis (RP), including recurrences (RRP) and progression to squamous cell carcinoma (SSC).

Materials and methods

A retrospective cohort of 25 laryngeal papilloma cases included 21 RRP, two of which progressed to SCC. Aberrant methylation status was determined using the multigene (22 tumor suppressor genes) methylation-specific multiplex ligationdependent probe amplification assay and confirmed using methylation specific PCR.


Twenty genes had altered DNA methylation in 22 of 25 cases. Aberrant methylation of CDKN2B and TIMP3 was most frequent. Promoter hypermethylation of BRCA2, APC, CDKN2A and CDKN2B was detected in 2 RRP cases with subsequent progression to SCC. Of the 25 cases, 22 were positive for HPV-6, 2 for HPV-11 and 1 for HPV-16 and 33.


Consistent aberrant methylation of multiple tumor suppressor genes contributes to the pathogenesis of laryngeal papillomas. Persistent aberrant DNA methylation events in 2 RRP cases that progressed to cancer indicate an epigenetic monoclonal progression continuum to SCC.

PDF Share
  1. Squamous papillomas of the larynx in adults. A review of 63 cases. Clin Otolaryngol Allied Sci 1983;8(2):109-19.
  2. Changes in human papillomavirus typing of recurrent respiratory papillomatosis progressing to malignant neoplasm. Arch Otolaryngol Head Neck Surg 1994;120(11):1273-76.
  3. CO(2) laser treatment in 244 patients with respiratory papillomas. Laryngoscope 2001;111(9):1639-44.
  4. Molecular transformation of recurrent respiratory papillomatosis: Viral typing and p53 overexpression. Ann Otol Rhinol Laryngol 2003;112(4):298-302.
  5. Spontaneous neoplastic transformation of laryngeal papilloma in adults. Otolaryngol Pol 1991;45(3):186-94.
  6. Viral etiology of juvenileand adult-onset squamous papilloma of the larynx. Proc Natl Acad Sci USA 1982;79(17):5425-29.
  7. Human papillomavirus and host variables as predictors of clinical course in patients with juvenile-onset recurrent respiratory papillomatosis. J Clin Microbiol 1997;35(12):3098-103.
  8. Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci USA 1983;80(2):560-63.
  9. Molecular identification of 7 human papillomavirus types in recurrent respiratory papillomatosis. Arch Otolaryngol Head and Neck Surg 2000;126(9):1119-23.
  10. Recurrent respiratory papillomatosis: The Manchester experience, 1974-1992. J Laryngol Otol 1994;108(3):226-29.
  11. Presence of human papillomavirus in squamous cell laryngeal carcinomas. A study of thirty-nine cases using polymerase chain reaction and in situ hybridization. Acta Otolaryngol 1996;116(6):900-05.
  12. Molecular events in the progression of recurrent respiratory papillomatosis to carcinoma. Arch Pathol Lab Med 2002;126(10):1184-88.
  13. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004;429(6990):457-63.
  14. An epigenetically derived monoclonal origin for recurrent respiratory papillomatosis. Arch Otolaryngol Head and Neck Surg 2007;133(7):684-92.
  15. Molecular Classification of Breast Carcinoma In Situ. Current Genomics 2006;7(8):523-32.
  16. Epigenetic events underlie the pathogenesis of sinonasal papillomas. Mod Pathol 2007;20(10):1019-27.
  17. Delineating genetic pathways of disease progression in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2003;129(7):702-08.
  18. Methylation of multiple genes as diagnostic and therapeutic markers in primary Head and Neck Squamous Cell Carcinoma Arch Otolaryngol Head Neck Surg 2007;133(11):1131-38.
  19. Detection of HPV in Japanese and Chinese oral carcinomas by in situ PCR. Oral Oncol 2001;37(2):146-52.
  20. Human papillomavirus as a risk factor for oral squamous cell carcinoma: A meta-analysis, 1982-1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91(6):622-35.
  21. High-risk human papillomavirus types and squamous cell carcinoma in patients with respiratory papillomas. Otolaryngol Head Neck Surg 1999;120(5):698-705.
  22. Malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 DNA and mutation of p53. Laryngoscope 1998;108(5):735-40.
  23. Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest 1998;101(6):1478-87.
  24. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): Inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003;9(4):407-15.
  25. Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3. Gene Ther 2003;10(3):234-42.
  26. Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration. Nat Genet 2004;36(9):969-77.
  27. DNA methylation and cancer. J Cell Physiol 2000;183(2):145-54.
  28. A gene hypermethylation profile of human cancer. Cancer Res 2001;61(8):3225-29.
  29. p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett's esophagus. Gastroenterology 2002;122(4):1113-21.
  30. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res 2001;61(8):3410-18.
  31. Fine-mapping loss of gene architecture at the CDKN2B (p15INK4b), CDKN2A (p14ARF, p16INK4a), and MTAP genes in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132(4):409-15.
  32. p16 mutation frequency and clinical correlation in head and neck cancer. Acta Otolaryngol 1999;119(2):285-88.
  33. 9p21 deletion correlates with recurrence in head and neck cancer. Head Neck 1998;20(2):113-18.
  34. Epigenetic events of disease progression in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132(6):668-77.
  35. Inactivation of the p14(ARF), p15(INK4B) and p16(INK4A) genes is a frequent event in human oral squamous cell carcinomas. Oral Oncol 2001;37(6):498-504.
  36. Epigenetic changes of tumor suppressor genes, P15, P16, VHL and P53 in oral cancer. Oncol Rep 2003;10(3):659-63.
  37. Differential gene methylation in undifferentiated nasopharyngeal carcinoma. Int J Oncol 2003;22(4):869-74.
  38. Status of reduced expression and hypermethylation of the APC tumor suppressor gene in human oral squamous cell carcinoma. Int J Mol Med 2005;15(4):597-602.
  39. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998;62(3):676-89.
  40. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 1999;91(15):1310-16.
  41. Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2001;2(3):196-206.
  42. Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer. Clin Cancer Res 2007;13(3):832-38.
  43. Laryngeal papillomas. Clin Dermatol 1985;3(4):130-38.
  44. HPV DNA typing of adult-onset respiratory papillomatosis. Laryngoscope 1990;100(6):639-42.
  45. Human papillomavirus type, proliferative activity, and p53: potential markers of aggressive papillomatosis. Arch Pathol Lab Med 2000;124(5):721-24.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.