Genomic characterization of sub-centimeter pulmonary nodules.

Abstract

e13530 Background: There has been a dramatic increase in the detection of indeterminate pulmonary nodules (IPNs), many of which are 10 mm or less in diameter. The management of subcentimeter pulmonary nodules remains controversial. Deciphering the genomic landscape of subcentimeter pulmonary nodules will provide critical insights to the mechanisms of carcinogenesis and pave the way for the early prevention and interception of lung cancer. Methods: We subjected 439 IPN samples including 249 subcentimeter pulmonary nodules (≤10 mm in diameter) and 190 larger pulmonary nodules (>10 and ≤30mm in diameter) to deep next generation sequencing by using customized panels of 1021 genes. Clinical parameters of these IPNs were collected. The genomic landscape of subcentimeter pulmonary nodules and differences from that of larger pulmonary nodules were defined. Results: The proportions of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (ADC) in the subcentimeter group and the larger nodule group were 2.81% vs 0.00%, 13.25% vs 0.80%, 28.92% vs 4.82% and 55.02% vs 70.68%, respectively. The most commonly mutated genes in subcentimeter group were in EGFR, ERBB2, BRAF, MED12 and MAP2K1. Compared with the larger nodule group, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and SMARCA4 ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF, MAP2K1, and TSC1 ( p< 0.05). In the subset of ADC, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and PIK3CA ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF ( p< 0.05). Clonal index analysis of driver genes in lung adenocarcinoma showed that the larger nodule group had more driver mutations, but the clonality index of BRAF was higher in the subcentimeter group ( p= 0.0014). Furthermore, in the subcentimeter nodule group, the mutation frequency of BRAF was significantly higher in pre-invasive group (AAH/AIS) than that in the invasive group (IAC). And BRAF and EGFR were significantly mutually exclusive ( q< 0.001) in subcentimeter nodules, which showed the subgroup with BRAF mutations was a special subtype. Conclusions: Our results provided the distinct mutation pattern of subcentimeter nodules and showed that BRAF could play different roles in early phase of lung carcinogenesis. It would be helpful for understanding the genomic evolution mechanisms underlying the progression and invasiveness of early lung adenocarcinoma.