From preinvasive to invasive: disecting the evolutionary secretary of early lung adenocarcinoma

Rong Yin and Siwei Wang

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Tumor invasiveness status in early stage lung adenocarcinoma (LUAD) reflects the malignant degree of cancer cells and is associated with clinical prognosis. The “real origin” of invasive components in early stage LUAD was revealed to be complicated (Izumchenko, E. et al. 2015), and further study suggested that driver genes and tumor microenvironment (TME) also play roles in the invasive progression (Sivakumar et al. 2017). In this work, we performed a systematic approach to investigate the relationship among tumor evolution, driver mutations and tumor-infiltrating lymphocytes (TILs) in malignant pulmonary nodules (MPNs).

Inspired by the previous study using micro-dissection method (Jamal-Hanjani M, et al. 2017), we constructed a Chinese population-based cohort (A Non-Interventional Systematic Study for the Non-small Cell Lung Cancer Tempo-spatial Heterogeneity, LuCaTH), and fifty-three T1 stage (tumor size ≤ 3 cm) LUAD cases were included in this study. Three evolutionary trajectories of pre-invasive and adjacent invasive MPN components were revealed. In evolution mode 1 (EM1), none of driver mutations are shared. In evolution mode 2 (EM2), most recent common ancestor harbors critical common events. Private driver alterations are restricted to the pre-invasive component (EM2A) and the invasive component (EM2B), respectively. We then observed differential intratumor heterogeneity and tumor sizes among these EMs.

EGFR is the most frequently mutated driver gene in Asian LUAD population. Surprisingly our data indicated that the abundance of EGFR mutations in the invasive component was significantly lower than that in the adjacent pre-invasive component. Further analysis demonstrated that truncal mutation abundance and dN/dS ratios in EGFR-mutated MPNs was also reduced compared with EGFR-wild type MPNs. All these results indicated a strong selective pressure on EGFR-mutated tumor cells during the acquisition of invasiveness. Subsequently, TME deconvolution analysis (TIMER method) and further immunohistochemistry indicated that B cells were present at higher levels in the invasive component than the adjacent pre-invasive component, while no significant differences of T cells between the two components were observed in the serial histological sections of MPNs. These findings sharpen the understanding about the higher infiltrating B lymphocyte abundance in the EGFR mutant lung cancer patients which were reported by our group previously (Wang, C. et al. 2018).

Overall, we found that there are diverse evolutionary trajectories during the acquisition of invasiveness in early stage LUAD. Harboring EGFR mutations is critical to the selective pressure resulting from TILs and further impacts the clinical prognosis. However, we also expected whole exome or genome sequencing and a larger sample size to investigate other critical genomic alterations during the progression of early stage LUAD. In addition, the biological function and mechanism of B cell infiltration remains unknown, which might indicate a novel potential theraputic strategy for early stage LUAD. 

Link to the paper: https://www.nature.com/articles/s41467-020-19855-x

Rong Yin

Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research