A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Early detection of NSCLC will improve its outcome. We previously identified genetic signatures whose genomic copy number aberrations were associated with early stage NSCLC. Here, we aimed to develop a panel of genes that could be detected in sputum for NSCLC early detection. We first optimized a panel of genes by using an in situ minichip for measuring changes of the signatures in sputum of a case-control cohort of 49 NSCLC patients, 49 patients with chronic obstructive pulmonary disease (COPD), and 49 healthy smokers. We then validated the genes in an independent cohort of 69 NSCLC patients and 65 noncancer subjects. The results were compared with those of sputum cytology. Fifteen genes showed significant differences of their copy number changes in sputum between NSCLC and both COPD and healthy subjects. A logistic regression model with the best prediction was built on the basis of 6 genes, ENO1, FHIT, HYAL2, SKP2, p16, and 14-3-3zeta. The composite of the 6 genes produced 86.7% sensitivity and 93.9% specificity in distinguishing stage I NSCLC patients from the noncancer individuals. Furthermore, the genes had higher sensitivity (86.9%) in identification of squamous cell carcinoma (SCC) than in adenocarcinoma of the lungs (80.8%; P < 0.05). Validation of the genes in the independent cohort confirmed their diagnostic power that also showed higher accuracy for lung SCCs than for sputum cytology. The gene panel could provide sputumbased markers that have the potential to improve early detection of lung SCCs.

Identification of ENO1 As a Potential Sputum Biomarker for Early-Stage Lung Cancer by Shotgun Proteomics

“…Sputum was collected from the participants as described in our previous reports 10, 11, 18-23 . Immediately after sputum sample was received, sputum supernatant was prepared as previously described 24 .…”

“…Numerous studies have shown that molecular genetic changes in the exfoliated respiratory epithelial cells of sputum could provide potential biomarkers for early stage lung cancer 56, 7, 8, 9, 10, 11 . The exfoliated epithelial cells in sputum mainly comprise 1), bronchial epitheliums that are derived from centrally located tumors that mainly are SCC, 2), respiratory epitheliums that may share clonally molecular genetic lesions with SCC tumors , however not directly shed from the primary SCC tumors.…”

“…Therefore, the bronchial epithelial cell-based analysis often provides higher accuracy for SCCs that are centrally located in the lungs compared with ACs that arise peripherally 56, 78, 9. 10, 11 .…”

“…10, 11 . However, few of the genetic and epigenetic analytic approaches in sputum have been integrated into clinical practice and shown an impact on reducing the mortality of NSCLC.…”

The Evolving Role of Tissue Biospecimens in the Treatment of Cancer

“…The detection of atypical cells in sputum cells prepared for cytologic examination for the screening of lung cancer is a proven method, but suffers from low sensitivity. The addition of genomic markers can raise the sensitivity of cancer detection to 86% and specificity to 93% (Jiang, 2010). When it comes to actual tumors, interobserver agreement has had a history of similar problems with at best, modest reproducibility.…”