Genetic and methylation status of CDKN2A (p14ARF/p16INK4A) 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 (p14ARF/p16INK4A) 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 p14ARF promoter hypermethylation in 100% of cases, followed by TP53 (96.3%) and p16INK4A (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 p14ARF/TP53 pathway, seems to be in the course of RRP development.

Clinical and treatment course of lung carcinoma from adult-onset recurrent respiratory papillomatosis with lung involvement: A case report.

Neoplasms induced by human papillomavirus (HPV) infection are generally associated to high-risk HPV types. Recurrent respiratory papillomatosis (RRP) is a rare and chronic HPV-related disease characterized by papillomatous lesions in the respiratory tract, usually affecting larynx. RRP rarely comprises malignant transformation since the low-risk HPV-6 and/or HPV-11 are the most commonly found in the disease. We described a case of one adult-onset RRP (29-year-old, female) with HPV-6 infection affecting vocal folds and extra-laryngeal sites. Computed tomographic scan of the chest revealed papillomatosis with pulmonary spread showing multiple nodules and cavities. Lung involvement later progressed to squamous cell carcinoma of the lung. Patient's pregnancy during investigations may have accelerated lung carcinoma development due to immunological changes. Immunohistochemistry revealed PD-L1 high expression in tumor biopsy and, after pregnancy, the oncology treatment included a combination of pembrolizumab (PD-L1 inhibitor) to chemotherapy and also radiotherapy, showing considerable results. Patient died due to lung cancer complications 15 months after cancer diagnosis. RRP management associated with lung involvement and poor prognostic outcome, such as lung carcinoma, is still a big challenge. In this report, we described the clinical and treatment course of RRP progression to highlight the need for attention to future patients.