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Identification of heritable rare variants associated with early-stage lung adenocarcinoma risk.
Fu, Rui; Zhang, Jia-Tao; Chen, Rong-Rong; Li, Hong; Tai, Zai-Xian; Lin, Hao-Xiang; Su, Jian; Chu, Xiang-Peng; Zhang, Chao; Qiu, Zhen-Bin; Chen, Zi-Hao; Tang, Wen-Fang; Dong, Song; Yang, Xue-Ning; Zhang, Guo-Qing; Zhao, Guo-Ping; Wu, Yi-Long; Zhong, Wen-Zhao.
Afiliação
  • Fu R; School of Medicine, South China University of Technology, Guangzhou, China.
  • Zhang JT; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Chen RR; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
  • Li H; GenePlus-Beijing Institute, Beijing, China.
  • Tai ZX; Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • Lin HX; GenePlus-Beijing Institute, Beijing, China.
  • Su J; GenePlus-Beijing Institute, Beijing, China.
  • Chu XP; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Zhang C; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Qiu ZB; School of Medicine, South China University of Technology, Guangzhou, China.
  • Chen ZH; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Tang WF; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Dong S; School of Medicine, South China University of Technology, Guangzhou, China.
  • Yang XN; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Zhang GQ; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Zhao GP; Department of Cardiothoracic Surgery, Zhongshan City People's Hospital, Zhongshan, China.
  • Wu YL; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • Zhong WZ; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Transl Lung Cancer Res ; 11(4): 509-522, 2022 Apr.
Article em En | MEDLINE | ID: mdl-35529798
Background: In East Asia, the number of patients with adenocarcinoma, especially those presenting with ground-glass nodules (GGNs), is gradually increasing. Family aggregation of pulmonary GGNs is not uncommon; however, genetic predisposition in these patients remains poorly understood and identification of genes involved in the cause of these early-stage lung cancers might contribute to understanding of the underlying mechanisms and potential prevention strategies. Methods: Fifty patients with early-stage lung adenocarcinoma (LUAD) presenting as GGNs and a first-degree family history of lung cancer (FHLC) from 34 independent families were enrolled into this study. Germline mutations of these patients were analyzed with whole exome sequencing (WES) and compared with age- and sex-matched 39 patients with sporadic lung cancer and 689 local healthy people. We used a stepwise variant filtering strategy, gene-based burden testing, and enrichment analysis to investigate rare but potentially pathogenic heritable mutations. Somatic tumor mutations were analyzed to consolidate germline findings. Results: In total, 1,571 single nucleotide variants (SNVs) and 238 frameshifts with a minor allele frequency (MAF) <0.01, which were rare, recurrent, and potentially damaging candidates, were finally identified through the filtering in the GGN cohort. Pathway analysis showed the extracellular matrix to be the top dysregulated pathway. Gene-based burden testing of these highly disruptive risk-conferring heritable variants showed that MSH5 [odds ratio (OR), 9.28, 95% confidence interval (CI): 2.49-35.87], MMP9 (OR, 8.11, 95% CI: 2.22-28.43), and CYP2D6 (OR, 8.09, 95% CI: 2.68-24.92) were significantly enriched in our cohort (P<0.05). The number of rare damaging germline variants in non-smoking patients was significantly higher than that of smoking-affected patients (Spearman's ρ=-0.39, P=0.02). Conclusions: Heritable, potentially deleterious, and rare candidate variants of MSH5, MMP9 and CYP2D6 were significantly associated with early-stage LUAD presenting with GGNs. Nonsmoking patients likely have a higher genetic predisposition to this type of cancer than smoking-affected patients. These results have extended our understanding of the underlying mechanisms of early-stage LUAD.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article