Abstract 3248: Genomic characterization of premalignant lung squamous cell carcinoma lesions

Abstract

Abstract Background: Lung squamous cell carcinoma (SqCC) arises in the epithelial layer of the bronchial airway and is often preceded by the development of premalignant lesions. However, not all premalignant lesions progress to lung SqCC and many will regress spontaneously. Understanding the somatic alterations and molecular subtypes associated with progression will allow us to identify biomarkers for early detection and develop therapeutic strategies for disease prevention and interception. Methods: Biopsies were obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and CT at the Roswell Park Cancer Institute. For each subject, multiple sites were sampled repeatedly over time. One biopsy from each region was sent for pathological review while another biopsy was taken for molecular studies. Whole-exome sequencing (WES) was performed at Uniform Services University to 120x coverage and RNA-seq was performed at Boston University School of Medicine. Results: The median number of somatic mutations across all premalignant lesions that underwent DNA-seq (150 biopsies from 20 subjects) was 0.45 per megabase and displayed a modest association with histological grade (p=0.05). The most frequently mutated known lung cancer genes included NOTCH1 (14%), TP53 (6%), FAT1 (3%), PIK3CA (2%), KRAS (<1%), and CDKN2A (<1%). One patient had a moderate dysplastic lesion without any detectable arm-level copy number changes or known cancer mutations. Six months later, this lesion had progressed to severe dysplasia and obtained many genomic alterations commonly observed in squamous cell carcinoma including 3q gain, 3p loss, and mutations in TP53, NOTCH1, and CDKN2A. Using RNA-seq, we identified 4 distinct molecular subtypes using 197 biopsies from 29 subjects. One subtype was enriched for samples with dysplasia histology, high basal cell content, and the “Classical” SqCC tumor gene expression subtype (p<0.001). These associations replicated in an independent set of 111 biopsies from 20 subjects. Genes associated with IFN-gamma signaling and T cell mediated immunity were down-regulated among lesions that persisted or progressed vs. those that regressed within the high-grade subtype. Staining of adjacent biopsies revealed that decreased expression of these immune pathways was associated with decreased numbers of CD4+ and CD8+ T cells within the lesions and surrounding tissue. Conclusions: The somatic alterations observed in known cancer genes may be among the earliest events in lung SqCC development and may be useful as biomarkers for early detection. Molecular classification of these lesions into molecular subtypes may lead to biomarkers of disease progression that could be used to identify at-risk patients for aggressive surveillance or for prevention trials. Citation Format: Joshua D. Campbell, Xijun Zhang, Catalina Perdomo, Sarah Mazzilli, Yaron Geshalter, Samjot S. Dhillon, Gang Liu, Sherry Zhang, Hanqiao Liu, Jessica Vick, Christopher Moy, Stefano Monti, Evan Johnson, Matthew Meyerson, Matthew Wilkerson, Clifton Dalgard, Suso Platero, Chris Stevenson, Marc Lenburg, Mary Reid, Jennifer Beane, Avrum Spira. Genomic characterization of premalignant lung squamous cell carcinoma lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3248.