Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

DNA copy number profiles of premalignant endobronchial lesions: a validated predictor for endobronchial cancer

ABSTRACT: Individuals who present with premalignant endobronchial lesions are considered at high risk of lung cancer. Nonetheless, premalignant lesions behave erratically and only a minority progresses towards lung cancer. Therefore, biomarkers need to be discovered that can aid in assessing an individual’s risk for subsequent cancer to better tailor treatment choices and avoid unnecessary follow-up procedures. We recently proposed a classifier of DNA copy number alterations (CNAs) at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3 as risk predictor for endobronchial cancer. The current study was set out to validate the classifier among an independent series of premalignant endobronchial lesions with various histological grades. A series of 36 endobronchial premalignant lesions (8 squamous metaplasia, and 28 various grades of dysplasia) identified during autofluorescence bronchoscopy of 12 case subjects who had carcinoma in situ or carcinoma (≥CIS) during follow-up bronchoscopy at the initial site and 24 control subjects who remained cancer-free, was subjected to array Comparative Genomic Hybridization (arrayCGH). DNA copy number profiles were related to lesion outcome. Prediction accuracy of the previously defined molecular classifier to predict endobronchial cancer in this series was determined. Unsupervised hierarchical clustering analysis revealed a significant association between cluster assignment and lesion outcome (p< 0.001), independent of histological grade, with quiescent profiles in controls (24/24) and aberrant profiles in the majority of cases (9/12). Our pre-defined classifier demonstrated 92% accuracy for predicting cancer outcome in the current sample series. Our validated classifier holds great promise for stratification of patients with premalignant endobronchial lesions for risk of subsequent cancer. Fresh frozen specimens of 36 premalignant endobronchial biopsies. Test samples were compared to an external pool of normal male/female reference DNA.

ORGANISM(S): Homo sapiens

SUBMITTER: Daoud Sie

PROVIDER: E-GEOD-45287 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

DNA copy number aberrations in endobronchial lesions: a validated predictor for cancer.

van Boerdonk Robert A A RA Daniels Johannes M A JM Snijders Peter J F PJ Grünberg Katrien K Thunnissen Erik E van de Wiel Mark A MA Ylstra Bauke B Postmus Pieter E PE Meijer Chris J L M CJ Meijer Gerrit A GA Smit Egbert F EF Sutedja Thomas G TG Heideman Daniëlle A M DA

Thorax 20131113 5

We recently identified a DNA copy number aberration (CNA)-based classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia. The current study was set out to validate the prediction accuracy of this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions. The study included 36 high-risk subjects who had endobronchial lesions of various histologic ...[more]

PMID: 24227199

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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

DNA copy number profiles of premalignant endobronchial lesions: a validated predictor for endobronchial cancer

Publications

DNA copy number aberrations in endobronchial lesions: a validated predictor for cancer.

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