Genomic instability in congenital lung malformations in children

Area of Science:

• Pulmonary Medicine
• Genetics
• Oncology

Background:

• Congenital lung malformations (CLMs) are rare developmental abnormalities of the lung.
• The association between CLMs and lung cancer suggests an underlying biological link.
• Understanding this relationship is crucial for early detection and prevention strategies.

Purpose of the Study:

• To investigate the biological relationship between congenital lung malformations and malignancy.
• To identify genetic alterations within CLMs that may predispose to cancer development.

Main Methods:

• Whole-genome sequencing was performed on biopsies from 12 CPAMs, 6 intralobar, and 2 extralobar sequestrations.
• Somatic Single Nucleotide Variants (SNVs) were identified and confirmed using Sanger sequencing and blood samples.
• Analysis included assessing genomic instability and specific tumor transformation-related SNVs.

Main Results:

• Ninety-five percent of CLMs exhibited genomic instability with multiple gene mutation clusters.
• Seven tumor transformation-related SNVs were found in 6 out of 20 CLMs.
• Rare SNVs linked to lung cancer were identified in the 5p15.33 region, upstream of the TERT oncogene, along with variants in RET, FANCA, and MET genes.

Conclusions:

• Genomic instability in CLMs is a significant predisposing factor for malignancy.
• Genetic variants associated with tumor development were present in 30% of CLMs, irrespective of histopathology.
• The combination of genomic instability, specific genetic variants, and carcinogen exposure may trigger lung cancer development in individuals with CLMs.