Genomic Profiling of Aggressive Pathologic Features in Lung Adenocarcinoma

Abstract

IntroductionPathologic features involving LVI (lympho-vascular invasion), PNI (perineural invasion), STAS (spread through air spaces), and Grade 3 pattern (from the International Association for the Study of Lung Cancer grading system) are related to having an aggressive phenotype and linked to poor prognosis. However, few studies have conducted in-depth analyses of these features simultaneously with genomic profiling. MethodsA total of 1559 sequencing of adenocarcinoma samples were included in the common driver mutations analysis, 1306 samples were brought into genomic mapping analysis. OncoSG's East Asian ancestry dataset was implemented for Tumor-Node-Metastasis-Biomarker (TNMB) classification and prognostic assessment. ResultsEGFR was more significantly prevalent in LVI negativity (P=0.021), STAS negativity (P=0.002), and moderate grade (P＜0.001). ALK was significantly interrelated with LVI (P=0.028), STAS (P<0.001), and poor grade (P<0.001); ROS1 and STAS positivity (P=0.031), poor grade (P=0.016) were significantly related. KRAS (P=0.003) and BRAF-V600E (P=0.002) were only significantly intertwined with poor grade. Apart from common driver mutations, TP53, CHEK2, KEAP1, PTEN, RB1, NF1 were significantly enriched in LVI samples (P＜0.05). TP53, PTEN, CTNNB1, HGF, NF1 were more prominent in STAS (P<0.01). TP53, LRP1B, NF1 were significantly more prevalent in Grade 3 pattern (P＜0.001). The mixture of STK11, PTEN, and TOP2A generated by exclusive mutations may be a potential predictor of TNMB categorization towards survival. The HR of stage II compared I of TNMB was 2.28 (95% CI 1.36-3.86, P＜0.001), while stage III compared II was 1.95 (95% CI 1.04-3.21, P=0.031). ConclusionsThis analysis demonstrated the correlation of pathologic features with common driver mutations, key mutations and canonical oncogenic signaling pathways. The data highlighted the similarities and differences among these features horizontally, and provide new insights in TNMB classification and prognostic assessment.

Note:
Funding declaration: This research was sponsored by National Natural Science Foundation of China Major Joint Project on Key scientific issues of lung Cancer (82241235, KY2023-537-02), Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (2017B030314120), National High-Level Talents Special Support Program (KA0120231004) and High-level Hospital Construction Project (DFJH201801).

Conflict of Interests: The authors have declared no financial conflicts of interest with the study stated.

Ethical Approval: The Ethics Committee of Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University authorized the research (2019-726H-1), and all subjects gave written informed consent.

Keywords: lung adenocarcinoma, Genomic profiling, Lympho-vascular invasion, Spread Through Air Spaces, Grade 3 pattern from IASLC grading system