AUTHOR=Ren Yijiu , Huang Shujun , Dai Chenyang , Xie Dong , Zheng Larry , Xie Huikang , Zheng Hui , She Yunlang , Zhou Fangyu , Wang Yue , Li Pengpeng , Fei Ke , Jiang Gening , Zhang Yang , Su Bo , Sweet-Cordero E. Alejandro , Tran Nhan Le , Yang Yanan , Patel Jai N. , Rolfo Christian , Rocco Gaetano , Cardona Andrés Felipe , Tuzi Alessandro , Suter Matteo B. , Yang Ping , Xu Wayne , Chen Chang 

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

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00288

DOI=10.3389/fonc.2019.00288

ISSN=2234-943X

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