Identification of heritable rare variants associated with early-stage lung adenocarcinoma risk

Rui Fu; Jia-Tao Zhang; Rong-Rong Chen; Hong Li; Zai-Xian Tai; Hao-Xiang Lin; Jian Su; Xiang-Peng Chu; Chao Zhang; Zhen-Bin Qiu; Zi-Hao Chen; Wen-Fang Tang; Song Dong; Xue-Ning Yang; Guo-Qing Zhang; Guo-Ping Zhao; Yi-Long Wu; Wen-Zhao Zhong

doi:10.21037/tlcr-21-789

Identification of heritable rare variants associated with early-stage lung adenocarcinoma risk

Transl Lung Cancer Res. 2022 Apr;11(4):509-522. doi: 10.21037/tlcr-21-789.

Authors

Rui Fu^#^{1

2}, Jia-Tao Zhang^#³, Rong-Rong Chen⁴, Hong Li⁵, Zai-Xian Tai⁴, Hao-Xiang Lin⁴, Jian Su², Xiang-Peng Chu², Chao Zhang^{1

2}, Zhen-Bin Qiu², Zi-Hao Chen^{1

2}, Wen-Fang Tang^{2

6}, Song Dong², Xue-Ning Yang², Guo-Qing Zhang⁵, Guo-Ping Zhao⁵, Yi-Long Wu², Wen-Zhao Zhong^{1

2}

Affiliations

¹ School of Medicine, South China University of Technology, Guangzhou, China.
² Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
³ The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
⁴ GenePlus-Beijing Institute, Beijing, China.
⁵ Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
⁶ Department of Cardiothoracic Surgery, Zhongshan City People's Hospital, Zhongshan, China.

^# Contributed equally.

Abstract

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.

Keywords: Lung cancer; adenocarcinoma; genetic predisposition; germline mutation; ground-glass nodule (GGN).