Lung cancer with family history have been increasing gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The genome predisposition of GGNs with lung cancer family history remains baffling.
This prospective study (NCT04220268) enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, which presenting as GGNs in computer tomography (CT) scans. We collected blood and tumor samples from 59 patients with GGNs and first-degree relative family history of lung cancer (FHLC) to investigated germline and somatic mutations by whole exome sequencing (WES). Pre-invasive neoplasia causal variants were detected by quality, classification, minor allele frequency (MAF), functional prediction, and family segregation filter. Validation was conducted in an external cohort of 669 healthy participants without cancer, and in 126 nonoverlapping susceptibility loci for lung carcinogenesis identified by recent genome-wide association studies (GWAS).
Eighty-five single nucleotide variants (SNVs) and 11 frameshifts were detected, which were rare, predicted as damaging, and presented in more than two families. Fifteen of them had been reported that were associated with high risk of lung cancer or deleterious function. The MAF of them were lower than 0.01 in a local health Asian cohort and human exome databases. Three of them were validated in 126 susceptibility loci for lung carcinogenesis. The number of the rare, damaging and repeatedly germline mutations in non-smoking patients were significantly higher than those in smoking patients (2436 vs 593, p<0.05). The number of these germline mutation showed no significant difference between the patients with pure GGNs and mixed GGNs (1298 vs 1333, p>0.05).
Patients with GGNs and FHLC may have inheritable carcinogenesis mutations. These variants may potentially contribute to the risk of pulmonary pre-invasive adenocarcinoma susceptibility in Chinese population.
The authors.
Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (Grant No. 2017B030314120), National Natural Science Foundation of China (Grant No. 81673031&No. 81872510), High-level Hospital Construction Project (DFJH201801), Guangdong Provincial People's Hospital Young Talent Project (No. GDPPHYTP201902).
R-R. Chen, Z-X. Tai, H-X. Lin: Full/Part-time employment: GenePlus-Beijing Institute, Beijing, China. All other authors have declared no conflicts of interest.