Germline Predisposition and Copy Number Alteration in Pre-stage Lung Adenocarcinomas Presenting as Ground-Glass Nodules.

Synchronous multiple ground-glass nodules (SM-GGNs) are a distinct entity of lung cancer which has been emerging increasingly in recent years in China. The oncogenesis molecular mechanisms of SM-GGNs remain elusive. We investigated single nucleotide variations (SNV), insertions and deletions (INDEL), somatic copy number variations (CNV), and germline mutations of 69 SM-GGN samples collected from 31 patients, using target sequencing (TRS) and whole exome sequencing (WES). In the entire cohort, many known driver mutations were found, including (21.7%), (14.5%), and (6%). However, only one out of the 31 patients had the same somatic missense or truncated events within SM-GGNs, indicating the independent origins for almost all of these SM-GGNs. Many germline mutations with a low frequency in the Chinese population, and genes harboring both germline and somatic variations, were discovered in these pre-stage GGNs. These GGNs also bore large segments of copy number gains and/or losses. The CNV segment number tended to be positively correlated with the germline mutations ( = 0.57). The CNV sizes were correlated with the somatic mutations ( = 0.55). A moderate correlation ( = 0.54) was also shown between the somatic and germline mutations. Our data suggests that the precancerous unstable CNVs with potentially predisposing genetic backgrounds may foster the onset of driver mutations and the development of independent SM-GGNs during the local stimulation of mutagens.