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Application of a classifier combining bronchial genomics and chest CT features facilitates the diagnostic evaluation of lung cancer in smokers and non-smokers

ABSTRACT: Introduction: Lung cancer screening by computed tomography (CT) reduces mortality but exhibited high false-positive rates. We established a diagnostic classifier combining chest CT features with bronchial genomics. Materials and Methods: Patients with CT-detected suspected lung cancer were enrolled. The sample collected by bronchial brushing was used for RNA sequencing. R software was applied to build the model. Results: A total of 283 patients, including 183 with lung cancer and 100 with benign lesions, were included. When incorporating genomic data with radiological characteristics, the advanced model yielded 0.903 AUC with 81.1% NPV. Moreover, the classifier performed well regardless of lesion size, location, stage, histologic type, or smoking status. Pathway analysis showed enhanced epithelial differentiation, tumor metastasis, and impaired immunity were predominant in smokers with cancer, whereas tumorigenesis played a central role in non-smokers with cancer. Apoptosis and oxidative stress contributed critically in metastatic lung cancer; by contrast, immune dysfunction was pivotal in locally advanced lung cancer. Conclusions: We devised a minimal-to-noninvasive, efficient diagnostic classifier for smokers and non-smokers with lung cancer, which provides evidence for different mechanisms of cancer development and metastasis associated with smoking. A negative classifier result will help the physician make conservative diagnostic decisions.

ORGANISM(S): Bronchus

PROVIDER: GSE166926 | GEO | 2021/02/18

REPOSITORIES: GEO

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Project description:Upregulation of Expression of the Ubiquitin Carboxyl Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers The microarray data deposited here is from 39 HG-U133 Plus 2.0 GeneChips, from 12 normal non-smokers, 12 phenotypic normal smokers, 9 Early COPD and 6 COPD individuals, all small airways, all small airway. A subset of these samples have been already submitted under GEO Accession Number GSE 4498. These are: 12 non-smokers samples (GSM101095-GSM101106) and 10 smoker samples (GSM101107-GSM101116). These 22 samples that are also in GSE4498 were described in Harvey, B-G; Heguy, A.; Leopold, P.L.; Carolan, B.; Ferris, B. and Crystal R.G. Modification of Gene Expression of the Small Airway Epithelium in Response to Cigarette Smoking. J. Mol. Med (in press). These data are part of a study aimed at understanding how cigarette smoking modifies neuroendocrine cells, in which microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals (normal nonsmokers, normal smokers, smokers with early COPD and smokers with established COPD). Of 11 genes considered to be neuroendocrine cell-specific, only ubiquitin C-terminal hydrolase L1(UCHL1), a member of the ubiquitin proteasome pathway, was consistently upregulated in smokers compared to nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemistry of bronchial biopsies of smokers compared to nonsmokers. Interestingly, however, while UCHL1 expression was present only in neuroendocrine cells of the airway epithelium in nonsmokers, UCHL1 expression was also expressed in ciliated epithelial cells in smokers, an intriguing observation in light of recent observations that ciliated cells can are capable of transdifferentiating to other airway epithelium. In the context that UCHL1 is involved in the degradation of unwanted, misfolded or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy. Keywords: non-smokers vs phenotypic normal smokers, smokers with early COPD, and smokers with COPD

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Application of a classifier combining bronchial genomics and chest CT features facilitates the diagnostic evaluation of lung cancer in smokers and non-smokers

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