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

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.

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.

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).

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.