An epigenetically derived monoclonal origin for recurrent respiratory papillomatosis.
OBJECTIVE
To investigate the contribution of promoter methylation-mediated epigenetic events in recurrent respiratory papillomatosis tumorigenesis.


METHODS
Archival tissue DNA, extracted from microdissected papilloma lesions, was interrogated for methylation status by means of the novel, multigene methylation-specific multiplex ligation-dependent probe amplification assay.


METHODS
Fifteen subjects with recurrent respiratory papillomatosis, 3 females and 12 males, all with adult onset of illness (age range, 23-73 years) except for 1 female patient with juvenile onset (1 year old).


RESULTS
Promoter hypermethylation was recorded in 14 of 15 cases, and 19 of 22 unique methylation-prone cancer genes in the multigene panel had altered DNA methylation in at least 1 laryngeal papilloma biopsy specimen. Identical abnormally methylated genes were found in 5 of 15 recurrent cases, of which the CDKN2B gene was hypermethylated in all 5 cases. Dissimilar epigenetic events were noted in the remaining cases.


CONCLUSIONS
A clonal origin was derived for 5 of 15 recurrent respiratory papillomatosis biopsy specimens based on identical epigenetic events. The high frequency of epigenetic events, characterized by consistent promoter hypermethylation of multiple tumor suppressor genes, points to the use of gene silencing mechanisms in the pathogenesis of recurrent respiratory papillomatosis.
Stephen
Josena Kunjoonju
JK
Department of Otolaryngology-Head and Neck Surgery, Henry Ford Hospital, 1 Ford Pl, 1D, Detroit, MI 48202, USA.
Vaught
Lori E
LE
Chen
Kang Mei
KM
Shah
Veena
V
Schweitzer
Vanessa G
VG
Gardner
Glendon
G
Benninger
Michael S
MS
Worsham
Maria J
MJ
D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D015331:Cohort Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D044127:Epigenesis, Genetic; D005260:Female; D017491:Genes, APC; D019942:Genes, p16; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D007822:Laryngeal Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015336:Molecular Probe Techniques; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D010212:Papilloma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C497446:VHL protein, human