Genetic and methylation status of CDKN2A (p14ARF/p16INK4A) and TP53 genes in recurrent respiratory papillomatosis

Mariana Chantre-Justino; Ingrid Gonçalves da Veiga Pires; Marcelo Cardoso Figueiredo; Aline Dos Santos Moreira; Gilda Alves; Maria Helena Faria Ornellas

doi:10.1016/j.humpath.2021.11.008

Genetic and methylation status of CDKN2A (p14^ARF/p16^INK4A) and TP53 genes in recurrent respiratory papillomatosis

Hum Pathol. 2022 Jan:119:94-104. doi: 10.1016/j.humpath.2021.11.008. Epub 2021 Nov 23.

Authors

Mariana Chantre-Justino¹, Ingrid Gonçalves da Veiga Pires², Marcelo Cardoso Figueiredo³, Aline Dos Santos Moreira⁴, Gilda Alves², Maria Helena Faria Ornellas²

Affiliations

¹ Circulating Biomarkers Laboratory, Pathology Department, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro 20550-170, Brazil. Electronic address: mari.chantre@gmail.com.
² Circulating Biomarkers Laboratory, Pathology Department, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro 20550-170, Brazil.
³ Respiratory Endoscopy and Head and Neck Surgery Service at Hospital Federal de Bonsucesso, Rio de Janeiro 21041-030, Brazil.
⁴ Laboratory of Functional Genomics and Bioinformatics, PTDIS/FIOCRUZ, Rio de Janeiro 21040-900, Brazil.

PMID: 34826422
DOI: 10.1016/j.humpath.2021.11.008

Abstract

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^ARF/p16^INK4A) 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^ARF promoter hypermethylation in 100% of cases, followed by TP53 (96.3%) and p16^INK4A (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^ARF/TP53 pathway, seems to be in the course of RRP development.

Keywords: DNA methylation; Recurrent respiratory papillomatosis; Somatic mutations; TP53; p14(ARF); p16(INK4A).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Biomarkers, Tumor / genetics*
Child
Child, Preschool
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
DNA Methylation*
DNA Mutational Analysis
Epigenesis, Genetic*
Female
Humans
Male
Middle Aged
Mutation*
Papillomavirus Infections / diagnosis
Papillomavirus Infections / genetics*
Polymerase Chain Reaction
Respiratory Tract Infections / diagnosis
Respiratory Tract Infections / genetics*
Tumor Suppressor Protein p14ARF / genetics*
Tumor Suppressor Protein p53 / genetics*
Young Adult

Substances

Biomarkers, Tumor
CDKN2A protein, human
Cyclin-Dependent Kinase Inhibitor p16
TP53 protein, human
Tumor Suppressor Protein p14ARF
Tumor Suppressor Protein p53

Supplementary concepts

Recurrent respiratory papillomatosis