Comprehensive characterization of genomic and radiologic features reveals distinct driver patterns of RTK/RAS pathway in pulmonary nodules presenting as ground-glass opacity.

Abstract

e20516 Background: GGO-associated pulmonary nodule has been known as radiological appearances of early stage and exhibit more indolent biological behavior. The correlation of different driver gene and radiological features remain poorly understood. Methods: We performed high-depth sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients with a custom 1021-gene panel. 130 were multiple pulmonary nodules from 58 patients (2-4 samples per patient). Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry and multiplex immunofluorescent staining were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Results: Mixed GGO enriched in the pathology of invasive LUAD comparing to pure GGO (182/216 vs 73/118, p < 0.001). 88.0% (294/334) of GGO-associated nodules carried at least one gene mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway and these driver genes were mutual exclusive to each other. T790M mutation was detected in one patient who had a nodule with CTR > 0.5 and was pathologically defined as MIA. 96.4% (54/56) multiple pulmonary nodules from the same patients showed distinct oncogenic alterations, but 72.4% (42/58) patients carried at least one mutant gene in RTK/RAS pathway across each pulmonary nodule. Nodules with ERBB2/ BRAF/ MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations, showing fewer mutations in radiology status of mGGO or pathology of invasive LUAD. KRAS-mutant subgroup possessed the highest expression of Ki-67 and PD-L1, more infiltration of CD4+ T cell and CD8+T cell. The second highest Ki67-expression was in EGFR-mutant subgroup, together with more CD8+T cell. For EGFR-mutant nodules, co-mutations with TP53 or RBM10 enriched in nodules with CTR > 0.5 and showing higher values of mean CT attenuation and TMB, which may relate to GGO evolution or invasiveness progression. Conclusions: This study elucidated a comprehensive genomic landscape of Chinese radiologically detected GGO-associated pulmonary nodules and highlighted different driver patterns of RTK/RAS pathway corresponding to radiologic features. Our findings provided valuable insight for further research on driver event of RTK/RAS pathway and cancer interception of GGO-associated pulmonary nodules.