Deep sequencing reveals the genomic characteristics of lung adenocarcinoma presenting as ground-glass nodules (GGNs).

BACKGROUND

The concept of multi-step progression from atypical adenomatous hyperplasia (AAH) to invasive adenocarcinoma (ADC) has been proposed, and ground-glass nodules (GGNs) may play a critical role during the early lung tumorigenesis. We present the first comprehensive description of the genomic architecture of GGNs to unravel the genetic basis of GGN.

METHODS

We investigated 30 GGN-like lungs ADC by performing >1,000× whole-exome sequencing (WES) and characterized the genomic variations and evaluate the relationship between the clinicopathologic and molecular characteristics in this disease.

RESULTS

Despite the low somatic mutation burden, GGNs exhibited high intratumor heterogeneity (ITH) characterized by the proportion of subclonal mutations. Different mutagenesis shaped the genomes of GGN during cancer evolution and were mostly featured by molecular clock-like signatures that occur in clonal mutations and defective DNA mismatch signatures that occur in subclonal mutations. Moreover, 10.7-67.1% clonal mutations occurred after whole-genome doubling (WGD), indicating that WGD could be a frequent truncal event in GGNs. Samples with WGD showed higher genomic instability but lower ITH. These GGNs were characterized by recurrent focal copy-number changes that are highly associated with tumorigenesis, with only two genes ( and ) that were recurrently mutated. Additionally, GGNs with different pathological subtypes or computed tomography (CT) features exhibited distinct genetic characteristics. Lepidic predominant or pure GGNs in CT images carried a lower mutation burden and had a relatively stable genome than nonlepidic or mixed GGNs. GGNs with mutations tended to accompany a pathologically lepidic pattern, indicating may drive the distinct subtype of lung cancer with better prognosis.

CONCLUSIONS

These findings facilitated interpreting the genomic characteristics of GGNs, provided insight into the early stages of lung cancer evolution, and possessed potential clinical significance.