Abstract
Background: Lung adenocarcinoma (LUAD) usually contain heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. A more comprehensive analysis involving discovery and public validation cohorts on the two subtypes could better decipher the key biological and evolutionary mechanisms.Methods: We firstly retrospectively studied the survival status of 286 LUAD patients with different subtypes. MIP and LEP components were micro-dissected for whole-exome sequencing (WES). Shared and private alterations as well as genomic alternation characteristics between the two components were investigated. Four public cohorts containing LEP and MIP samples were further selected for genomic profile comparison, novel therapeutic target investigation and immune infiltration quantification.Results: LEP and MIP subtypes exhibited largest disease free survival (DFS) in our patients. A total of 2035 SNV and 2757 InDels were identified in the sequenced LEP and MIP components. EGFR was found with highest mutation frequency. Distinct biological processes or pathways were involved in the evolutionary of the two components. Besides, analyses on copy number variation (CNV) and intratumor heterogeneity further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level ITH and the pervasive DNA Damage Response as well as WNT pathway gene alternations in MIP component. Phylogenetic analysis on 5 pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analysis in our samples and public cohorts, PTP4A3, NAPRT and RECQL4 were identified as novel therapeutic and diagnostic targets in MIP subtype. Immunosuppression prevalence in MIP component was finally confirmed by multi-omics data.Conclusion: We identified genetic differences responsible for variated prognosis. The subtype evolution trajectory was additionally unraveled. Novel gene targets and the immunological analyses also provided therapeutic suggestions for MIP subtype.
Correction: Quantitative Computed Tomographic Descriptors Associate Tumor Shape Complexity and Intratumor Heterogeneity with Prognosis in Lung Adenocarcinoma
