Abstract A15: Nasal gene expression for the diagnostic evaluation of indeterminate pulmonary nodules within a screening population
Authors: Steiling Katrina , Zhang Jiarui , Sands Jacob , Sullivan Travis , Billatos Ehab , Moses Elizabeth , Liu Gang , Lamb Carla , McKee Brady , Lenburg Marc , Spira Avrum , Rieger-Christ Kimberly 
Published: February 2019

Abstract
Introduction: Lung cancer remains the leading cause of cancer-related death due to the limited ability to detect the disease at an early and potentially curable stage. CT lung screening (CTLS) of high-risk patients improves mortality. However, the high proportion of false-positive tests, the majority of which are indeterminate pulmonary nodules (IPNs), has limited widespread adoption of this life-saving screening modality. Since screen-detected IPNs contribute to the overall cost of screening and potential morbidity due to the need for further diagnostic testing, there is an urgent need for accurate tools to stratify patients with screen-detected nodules for routine follow-up or additional intervention. Prior work from our group has identified alterations in nasal epithelial cell gene expression in individuals undergoing bronchoscopy, which are associated with lung cancer. In this study, we are evaluating the ability of nasal epithelial gene expression to identify patients with lung cancer among CTLS patients with IPNs.
Methods: Nasal epithelial brushings were collected from a screening cohort at Lahey Hospital & Medical Center (LHMC) with CTLS IPNs (6-20mm; n=38) that had been followed prospectively for up to 2 years (19 lung cancers; 19 benign disease). We performed total RNA sequencing on the nasal samples using the Illumina TruSeq Stranded Total RNA Sample Preparation kit. Reads were aligned to the human assembly Genome Reference Consortium Human Build 37 to identify a gene signature associated with cancer status. To evaluate the signature in an independent IPN cohort, nasal epithelial brushings were collected from current and former smokers (n=67; age&gt;45, pack-year&gt;20) undergoing diagnostic workup for IPNs (7-30 mm) at military and VA hospitals within the DECAMP consortium. Subjects were followed prospectively for up to two years after sample collection until a final diagnosis of lung cancer (n=38) or benign disease (n=29) was made.
Results: Using a generalized linear model correcting for smoking status, we identified 39 differentially expressed genes (DEGs, FDR-q &lt; 0.1) from the nasal epithelium associated with lung cancer status. Genes upregulated in individuals with lung cancer were enriched for pathways related to keratinization, TNFα signaling, hypoxia, p53 signaling and KRAS signaling, while downregulated genes in lung cancer patients were enriched for pathways related to ciliary function (GSEA FDR &lt; 0.01). Unsupervised clustering of these DEGs across the independent IPN cohort demonstrated significant separation of samples from individuals with a final diagnosis of lung cancer and those with benign pulmonary nodules (Chi squared test &lt; 0.05).
Conclusion: Our findings suggest that there are nasal gene expression alterations associated with lung cancer diagnosis among CTLS patients with indeterminate pulmonary nodules. These alterations may be leveraged to develop a nasal biomarker for the early detection of lung cancer in high-risk smokers.
Citation Format: Katrina Steiling, Jiarui Zhang, Jacob Sands, Travis Sullivan, Ehab Billatos, Elizabeth Moses, Gang Liu, Carla Lamb, Brady McKee, Marc Lenburg, Avrum Spira, Kimberly Rieger-Christ. Nasal gene expression for the diagnostic evaluation of indeterminate pulmonary nodules within a screening population [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A15.