Whole-Genome Methylation Study of Congenital Lung Malformations in Children.

Sara Patrizi,Adamo Pio D’Adamo,Federica Pederiva

doi:10.3389/fonc.2021.689833

Abstract

Background and ObjectivesThe treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy.MethodsThe DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparisons between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls and between a pleuropulmonary blastoma (PPB) and controls were performed. Moreover, each malformed sample was pairwise compared with its respective control. All differentially methylated regions (DMRs) with an adjusted p-value <0,05 were studied.ResultsEvery comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors.ConclusionsMethylation anomalies already described in lung tumors and also shared by the PPB were found in congenital lung malformations, regardless the histology. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation.

Highlights

There is a general consensus that symptomatic congenital pulmonary malformations (CPMs) should be removed surgically
Using Illumina MethylationEPIC array analysis that is easy to use, time efficient, and cost effective technique [12], we studied all differentially methylated regions (DMRs) in a series of congenital lung malformations in an attempt to find methylation anomalies in genes already described in association with malignancy
Samples used as control included biopsies from macroscopically normal lung tissue adjacent to the malformation of seven patients, three with intralobar sequestration (ILS) and four with congenital pulmonary airway malformation type 2 (CPAM2) and from the lung of a patient who was thought to have a congenital malformation until histological analysis proved the tissue to be normal

Summary

Introduction

There is a general consensus that symptomatic congenital pulmonary malformations (CPMs) should be removed surgically. The treatment of asymptomatic patients remains controversial [1]. The relationship between congenital lung malformations and malignancy remains undefined and continues to be a critical consideration in surgical decision making. Hartman and Stochat reported that 4% of pulmonary malignant tumors were associated with congenital cystic malformations. Tumors developing within these malformations included rhabdomyosarcoma, pleuropulmonary blastoma (PPB), adenocarcinoma, squamous cell carcinoma, and mesenchymoma [4]. Ozcan et al reported 29 cases of primary rhabdomyosarcoma, 15 of which arose in a preexisting congenital lung malformations [5]. The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. We studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy

Objectives

Methods

Results

Conclusion