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

  • Author(s): 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
  • et al.

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.

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