Germline predisposition and copy number alteration in pre-stage lung adenocarcinomas presenting as ground-glass nodules

Yijiu Ren, Shujun Huang, Chenyang Dai, Dong Xie, Larry Zheng, Huikang Xie, Hui Zheng, Yunlang She, Fangyu Zhou, Yue Wang, Pengpeng Li, Ke Fei, Gening Jiang, Yang Zhang, Bo Su, E. Alejandro Sweet-Cordero, Nhan Tran, Yanan D Yang, Jai N. Patel, Christian Rolfo & 7 others Gaetano Rocco, Andrés Felipe Cardona, Alessandro Tuzi, Matteo B. Suter, Ping Yang, Wayne Xu, Chang Chen

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number288
JournalFrontiers in Oncology
Volume9
Issue numberMAR
DOIs
StatePublished - Jan 1 2019

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Glass
Germ-Line Mutation
Mutation
Exome
Mutagens
Adenocarcinoma of lung
China
Lung Neoplasms
Carcinogenesis
Nucleotides
Population
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Germline predisposition and copy number alteration in pre-stage lung adenocarcinomas presenting as ground-glass nodules. / 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; Alejandro Sweet-Cordero, E.; Tran, Nhan; Yang, Yanan D; Patel, Jai N.; Rolfo, Christian; Rocco, Gaetano; Cardona, Andrés Felipe; Tuzi, Alessandro; Suter, Matteo B.; Yang, Ping; Xu, Wayne; Chen, Chang.

In: Frontiers in Oncology, Vol. 9, No. MAR, 288, 01.01.2019.

Research output: Contribution to journalArticle

Ren, Y, Huang, S, Dai, C, Xie, D, Zheng, L, Xie, H, Zheng, H, She, Y, Zhou, F, Wang, Y, Li, P, Fei, K, Jiang, G, Zhang, Y, Su, B, Alejandro Sweet-Cordero, E, Tran, N, Yang, YD, Patel, JN, Rolfo, C, Rocco, G, Cardona, AF, Tuzi, A, Suter, MB, Yang, P, Xu, W & Chen, C 2019, 'Germline predisposition and copy number alteration in pre-stage lung adenocarcinomas presenting as ground-glass nodules', Frontiers in Oncology, vol. 9, no. MAR, 288. https://doi.org/10.3389/fonc.2019.00288
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 ; Alejandro Sweet-Cordero, E. ; Tran, Nhan ; Yang, Yanan D ; Patel, Jai N. ; Rolfo, Christian ; Rocco, Gaetano ; Cardona, Andrés Felipe ; Tuzi, Alessandro ; Suter, Matteo B. ; Yang, Ping ; Xu, Wayne ; Chen, Chang. / Germline predisposition and copy number alteration in pre-stage lung adenocarcinomas presenting as ground-glass nodules. In: Frontiers in Oncology. 2019 ; Vol. 9, No. MAR.
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title = "Germline predisposition and copy number alteration in pre-stage lung adenocarcinomas presenting as ground-glass nodules",
abstract = "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.",
author = "Yijiu Ren and Shujun Huang and Chenyang Dai and Dong Xie and Larry Zheng and Huikang Xie and Hui Zheng and Yunlang She and Fangyu Zhou and Yue Wang and Pengpeng Li and Ke Fei and Gening Jiang and Yang Zhang and Bo Su and {Alejandro Sweet-Cordero}, E. and Nhan Tran and Yang, {Yanan D} and Patel, {Jai N.} and Christian Rolfo and Gaetano Rocco and Cardona, {Andr{\'e}s Felipe} and Alessandro Tuzi and Suter, {Matteo B.} and Ping Yang and Wayne Xu and Chang Chen",
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T1 - Germline predisposition and copy number alteration in pre-stage lung adenocarcinomas presenting as ground-glass nodules

AU - Ren, Yijiu

AU - Huang, Shujun

AU - Dai, Chenyang

AU - Xie, Dong

AU - Zheng, Larry

AU - Xie, Huikang

AU - Zheng, Hui

AU - She, Yunlang

AU - Zhou, Fangyu

AU - Wang, Yue

AU - Li, Pengpeng

AU - Fei, Ke

AU - Jiang, Gening

AU - Zhang, Yang

AU - Su, Bo

AU - Alejandro Sweet-Cordero, E.

AU - Tran, Nhan

AU - Yang, Yanan D

AU - Patel, Jai N.

AU - Rolfo, Christian

AU - Rocco, Gaetano

AU - Cardona, Andrés Felipe

AU - Tuzi, Alessandro

AU - Suter, Matteo B.

AU - Yang, Ping

AU - Xu, Wayne

AU - Chen, Chang

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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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