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Objective:  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.   Methods:  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).   Results:  In the entire cohort, many known driver mutations were found, including  EGFR  (21.7%),  BRAF  (14.5%), and  KRAS  (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 ( r  = 0.57). The CNV sizes were correlated with the somatic mutations ( r  = 0.55). A moderate correlation ( r  = 0.54) was also shown between the somatic and germline mutations.   Conclusion:  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.

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