Unknown,Transcriptomics,Genomics,Proteomics

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Profiling premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis

ABSTRACT: Lung squamous cell carcinoma (SCC) is thought to arise from premalignant lesions in the airway epithelium, therefore studying these lesions is critical for understanding lung carcinogenesis. We performed RNA sequencing on laser-microdissected representative cell populations along the SCC pathological continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. This is the first gene expression profiling of airway premalignant lesions with patient-matched samples that provides insight into the mechanisms of stepwise lung carcinogenesis. Profiling of mRNA expression in laser-microdissected normal airway basal cells, premalignant airway lesions, and lung SCC tumor cells by massively parallel RNA sequencing.

ORGANISM(S): Homo sapiens

SUBMITTER: Adam Gower

PROVIDER: E-GEOD-49155 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Molecular profiling of premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis.

Ooi Aik T AT Gower Adam C AC Zhang Kelvin X KX Vick Jessica L JL Hong Longsheng L Nagao Brian B Wallace W Dean WD Elashoff David A DA Walser Tonya C TC Dubinett Steven M SM Pellegrini Matteo M Lenburg Marc E ME Spira Avrum A Gomperts Brigitte N BN

Cancer prevention research (Philadelphia, Pa.) 20140311 5

Lung squamous cell carcinoma (SCC) is thought to arise from premalignant lesions in the airway epithelium; therefore, studying these lesions is critical for understanding lung carcinogenesis. Previous microarray and sequencing studies designed to discover early biomarkers and therapeutic targets for lung SCC had limited success identifying key driver events in lung carcinogenesis, mostly due to the cellular heterogeneity of patient samples examined and the interindividual variability associated ...[more]

PMID: 24618292

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Project description:Exposure to cigarette smoke creates a field of injury throughout the entire respiratory tract inducing genomic alterations that lead to an “at-risk” airway where and lung cancers develop. Lung squamous cell carcinoma (SCC) arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions(PMLs). The presence of high-grade persistent or progressive PMLs is a marker of increased lung cancer risk both at the lesion site elsewhere in the lung. Effective tools to identify and treat premalignant lesions at highest risk of progression to invasive carcinoma are lacking. We profiled via RNA-Seq airway brushing and biopsies (divided into two cohorts: discovery and validation) obtained from high-risk smokers undergoing lung cancer screening via serial auto-fluorescence bronchoscopy procedures. We identified four distinct molecular subtypes (Proliferative, Inflammatory, Secretory, and Normal) in the bronchial biopsies that correspond to a spectrum of biological and morphological alterations. The Proliferative subtype was enriched with dysplastic PMLs from current smokers that exhibit up-regulation of KRT5 and KI67 as well as metabolic and cell cycle pathways, and down-regulation of cilium-associated processes and FOXJ1 expression. Molecular subtype classification in the validation cohort biopsies replicated these significant clinical and biological associations. Airway brushes from normal fluorescing areas of the large airway classified as the Proliferative subtype specifically predicts the presence of biopsies of this same subtype. Within the Proliferative subtype, genes associated with interferon signaling and antigen processing and presentation were observed to be down-regulated among dysplastic biopsies that persistent or progress in the future. Innate and adaptive immune cells were computationally predicted to be depleted in these biopsies and this was confirmed via immunofluorescence staining of adjacent biopsies. These findings provide a proof of concept that molecular biomarkers of endobronchial biopsies can enhance histopathological grading and that immunoprevention strategies are an important future direction in intercepting the progression of PMLs to lung cancer.

Dataset Information

Profiling premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis

Publications

Molecular profiling of premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis.

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