Genomic instability in congenital lung malformations in children
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In brief
In brief
This study reveals that 95% of congenital lung malformations (CPAMs and sequestrations) exhibit genomic instability, with 30% harboring tumor-associated genetic variants including mutations near the TERT oncogene and in RET, FANCA, and MET genes. These findings suggest CLMs may predispose to malignancy when combined with carcinogen exposure, potentially explaining the observed association between congenital lung lesions and subsequent lung cancer development.
- 95% of congenital lung malformations showed genomic instability with multiple clusters of mutated cells on whole-genome sequencing.
- 30% of CLMs harbored tumor transformation-related variants in genes like RET, FANCA, MET, and the 5p15.33 region near TERT oncogene.
- Genomic instability was present regardless of histopathology type (CPAM, intralobar or extralobar sequestration).
- CLMs may represent a pre-malignant state that increases lung cancer risk when combined with carcinogen exposure.
- Routine resection of asymptomatic CLMs may be justified given the molecular evidence of malignant potential.
Written by the GCMD Library team from the article.
Abstract
Purpose
To study the biological relationship between congenital lung malformations (CLMs) and malignancy.
Methods
Biopsies of 12 CPAMs, 6 intralobar sequestrations and 2 extralobar sequestrations were analyzed through whole-genome sequencing. Blood samples from 10 patients were used to confirm or exclude somatic mosaicism. Putative somatic Single Nucleotide Variants (SNVs) were called for each malformed sample with a Panel of Normals built with control DNA samples extracted from blood. The variants were subsequently confirmed by Sanger sequencing and searched, whenever possible, in the blood samples of patients.
Results
All CLMs but one presented a signature of genomic instability by means of multiple clusters of cells with gene mutations. Seven tumor transformation-related SNVs were detected in 6/20 congenital lung malformations. Four very rare in the general population SNVs were found in a region previously linked to lung cancer in 5p15.33, upstream of TERT oncogene. Furthermore, we identified missense genetic variants, whose tumorigenic role is well known, in the RET, FANCA and MET genes.
Conclusions
Genomic instability in 95% of CLMs and genetic variants linked to tumor development in 30% of them, regardless of histopathology, are predisposing factors to malignancy, that combined with exposure to carcinogens, might trigger the development of malignancy and explain the association between CLMs and lung cancer.