Genetic and methylation status of CDKN2A (p14/p16) and TP53 genes in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare and chronic disease affecting the upper airway with papillomatous lesions caused by the human papillomavirus (HPV) infection, especially HPV-6 and/or HPV-11 types. Little is known about the genetic and epigenetic drivers in RRP pathophysiology. For this purpose, we analyzed 27 papillomatous lesions from patients with RRP to evaluate somatic mutations and methylation status in CDKN2A (p14/p16) and TP53, which are key tumor suppressor genes for the cell cycle control. Sanger sequencing analysis revealed one somatic mutation in TP53 (c.733_734insA) and four mutations in CDKN2A (c.-30G > T, c.29_30insA, c.69delT, and c.300C > A). These mutations were observed in 10 patients, 6 of which carried double mutation. Furthermore, 50% (5/10) of these patients carrying somatic mutations had RRP severity, representing 62.5% (5/8) of the severity cases in this study, albeit no significant association was found between somatic mutations and disease severity. Methylation-specific polymerase chain reaction assays revealed p14 promoter hypermethylation in 100% of cases, followed by TP53 (96.3%) and p16 (55.6%), suggesting the influence of HPV in the DNA methylation machinery. In conclusion, somatic mutations were not common events identified in patients with RRP. However, epigenetic modulation by high methylation rates, particularly for the p14/TP53 pathway, seems to be in the course of RRP development.