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M. Lenburg
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.07 - The Airway Field of Injury Reflects Metabolic Changes Associated with the Presence of Lung Squamous Premalignant Lesions (ID 2251)
16:45 - 18:15 | Author(s): M. Lenburg
- Abstract
Background:
Lung SCC arises in the epithelial layer of the bronchial airways and is preceded by the development of premalignant lesions (PMLs). The molecular events involved in the progression of PMLs to lung SCC are not clearly understood as not all PMLs that develop go on to form carcinoma. Our group is using high-throughput genomic techniques to characterize the process of premalignant progression by examining PMLs and non-lesion areas of individuals with PMLs (“field of injury”) to identify events that lead to the development of SCC. Pathway analysis revealed enrichment oxidative phosphorylation (OXPHOS) /respiratory electron transport among genes up-regulated in the airways of subjects with PMLs. OXPHOS is the most efficient metabolic pathway that generates energy in the form of ATP by utilizing the structures and enzymes of the mitochondria. OXPHOS is often elevated during epithelial tissue repair and is superseded by glycolysis in the development of cancer.
Methods:
mRNA-Seq was conducted on cytologically normal airway epithelium collected from indviduals with (n=50) and without (n=25) PMLs. Linear modeling strategies were used to identify genes altered between subjects with and without PMLs (n=206 out of 13,900, genes at FDR<0.001). Pathway analysis by GSEA revealed enrichment (FDR<0.05) of oxidative phosphorylation (OXPHOS)/respiratory electron transport genes among genes up-regulated in subjects with PMLs. To validate these findings, we examined oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) in primary airway epithelial cells cultures from PMLs and non-lesion areas and cancer cell lines that have high OXPHOS/ moderate glycolytic (H1299), moderate OXPHOS/ high glycolytic (HCC4006) or low OXPHOS/ low glycolytic (H2085) gene expression. In addition, protein expression of genes elevated in the field of injury including, translocase of the outer mitochondrial membrane (TOMM 22) and cytochrome C oxidase (COX-IV) were measured in FFPE sections of human PMLs and PMLs from the N-nitroso-tris-chloroethylurea (NTCU) mouse model of lung SCC.
Results:
OCR and ECAR values in the lung cancer cell lines were consistent with gene expression patterns. Perturbations of OXPHOS resulted in 3 fold (H1299) and 2 fold (HCC4006) higher OCR vales than those in H2085 cells (p<0.05) reflecting higher OXPHOS activity. Whereas the ECAR values were 2.5 fold (HCC4006) and 1.5 fold (H1299) higher than those in H2085 cells (p<0.05), reflecting higher glycolytic metabolism. The OCR and ECAR patterns in the primary premalignant cultures also supported the computational findings in the field of injury of PMLs. The baseline OCR/ECAR values were 1.5 fold higher in the cultures from PMLs compared to non-lesions controls (p<0.001). Additionally the OCR and ECAR values were elevated in response to perturbations in OXPHOS in the PMLs compared to controls. Protein levels of TOMM 22, and COX-IV were found to be elevated in dysplastic lesions compared to controls.
Conclusion:
Together these data suggest that metabolism-associated gene expression is correlated with cellular metabolism and there is an increase in OXPHOS associated with the development of PMLs. Furthermore, there is potential that therapeutically increasing or maintaining OXPHOS in premalignant lesions or the field of injury may be a mechanism of prevention for lung cancer.
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ORAL 39 - Potential Biomarkers for CT Screening (ID 149)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
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ORAL39.07 - A Bronchial Genomic Classifier Measured in Airway Epithelial Cells Improves Diagnostic Sensitivity of Bronchoscopy for Lung Cancer (ID 2215)
16:45 - 18:15 | Author(s): M. Lenburg
- Abstract
- Presentation
Background:
Bronchoscopy is often used for the diagnosis of lung cancer however its sensitivity is imperfect, especially for small and peripheral lesions. Adjunctive methods to improve the sensitivity of cancer detection would reduce the need for more invasive follow-up procedures when bronchoscopy is non-diagnostic. It has previously been shown that gene expression of cytologically-normal bronchial airway epithelial cells is altered in smokers with lung cancer. In this study we evaluated the performance of a bronchial genomic classifier to predict malignancy in an independent cohort of suspect lung cancer patients.
Methods:
A bronchial genomic classifier consisting of the expression of 23 genes measured in the airway epithelium was evaluated in a previously published, independent cohort (n=163) of current and former undergoing bronchoscopy for suspect lung cancer. In cases where bronchoscopy was non-diagnostic for malignancy, the performance of the classifier was evaluated using ROC-AUC, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
Results:
In the test set, bronchoscopy led to a diagnosis in 40 of 78 patients with cancer (sensitivity=51%, 95% CI 40-63%). The combination of the classifier with bronchoscopy improved the sensitivity to 96% (95% CI 89-99%; p <0.001); see Table. The prediction accuracy of the classifier was similar in lesions <3cm, as well as across cancer stage and histology. Among the 123 patients with a non-diagnostic bronchoscopy, 38 were ultimately diagnosed with lung cancer (prevalence of 31%). In this group of patients, the classifier had an AUC of 0.81 (95% CI, 0.73-0.88), accurately identifying 35 of the 38 lung cancer patients (sensitivity=92%; 95% CI, 78-98%), and 45 of 85 patients with benign lesions (specificity=53%; 95% CI, 42-63%). Of the 48 patients with a negative classifier result, 45 were diagnosed with benign lesions (NPV=94%, 95% CI 83-99%).Table. Performance of bronchoscopy, classifier, and the combined procedures in the test set
a) The performance of the classifier was evaluated for patients in whom bronchoscopy did not result in a finding of lung cancer (n=123).Category Bronchoscopy Classifier[a] Combined Total, N 163 123 163 Lung Cancer, N 78 38 78 Benign Lesion, N 85 85 85 Sens. (95% CI) 51% (40-62%) 92% (78-98%) 96% (89-99%) Spec. (95% CI) 100% (95-100%) 53% (42-63%) 53% (42-63%) NPV (95% CI) 69% (60-77%) 94% (83-99%) 94% (83-98%) PPV (95% CI) 100% (90-100%) 47% (36-58%) 65% (56-73%)
Conclusion:
A gene expression classifier measured in bronchial epithelial cells is able to accurately identify those at low risk for lung cancer in patients who have undergone bronchoscopy with non-diagnostic results. Due to the high sensitivity and NPV of the classifier, it could potentially inform clinical decisions regarding the need for further invasive testing for lung cancer in patients whose bronchoscopy is non diagnostic.
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