Abstract 2536: Mutational landscape of the bronchial epithelium of individuals at high risk for lung cancer
Authors: Rahman SM Jamshedur , Zhao Shilin , Chu Shih-Kai , Zou Yong , Hui Angela B. , Stricker Thomas P. , Heidi Chen , Diehn Maximilian , Massion Pierre P. 
Published: July 2021

Abstract
Insights into mutational burden of the airway epithelium, the field of cancerization, may play important role in stratifying individuals at different levels of risk for lung cancer. We hypothesized that cytologically normal bronchial epithelium of patients with lung cancer and those at high risk for lung cancer harbor driver mutations. We performed next generation sequence-based targeted CAPP-Seq (CAncer Personalized Profiling by deep Sequencing) and whole exome sequencing (WES) of DNA from the bronchial epithelial cells from the bronchial brushings of individuals at-risk for lung cancer and patients with lung cancer as well as matched lung tumor tissues. We used the Tammemagi risk model to calculate the risk for lung cancer. Both CAPPSeq and WES data analyses showed higher mutation burden in lung tumor tissues compared to bronchial brushings. Using targeted CAPPSeq, a total of 129 nonsynonymous mutations were identified in bronchial brushings. Among individuals without lung cancer, 9 oncogenic driver mutations were identified in 5 out of 13 high risk and 2 out of 7 low risk individuals. Among individuals with cancer, 13 out of 22 brushings harbored 11 driver mutations, of which mutations in TP53 and PTEN were identified in both tumor and brushing matched samples. Mutations detected in the brushings of individuals with and without cancer were TP53, PIK3CA, NOTCH1, KRAS, MET, CUL3, and NF1. Using WES on the DNA from the same brushings (low risk, n=9; high risk, n=8 and lung cancer, n=17), we identified 19478 mutations total, and 90 of that were also identified by CAPPSeq. WES identified 80% of the mutations that were identified by CAPPSeq with &gt;5% variant allelic frequencies (VAF). Mutations identified by CAPPSeq had VAF as low as 0.2% and vast majority of the mutations identified by WES had VAF &gt;5%. Out of 9 mutations in TP53 identified in the brushings by CAPPSeq, 4 were identified by WES. Mutation in KMT2D, a histone methylation enzyme and believed to be a tumor suppressor, was identified by WES in the brushings and the tumor tissues of patients with lung cancer as well as in one high risk brushings. Mutational signature profiling identified tobacco mutational signature in the bronchial epithelium and tobacco, APOBEC and DNA-DSB repair signatures in the tumor tissues. Copy number variation (CNV) data analysis revealed significantly higher CNV levels in tumor samples than brushing samples. Genome-wide CNA profiling identified regions significantly influenced by CNV, such as deletions in chromosome region 19p13.3, which was previously reported to be related to lung cancer. We identified mutations in cancer driver genes in the bronchial brushings of individuals with and without lung cancer. This field of cancerization effect may provide a tool for risk assessment for lung cancer. This research was funded by U01CA196405 to PPM.
Citation Format: SM Jamshedur Rahman, Shilin Zhao, Shih-Kai Chu, Yong Zou, Angela B. Hui, Thomas P. Stricker, Chen Heidi, Maximilian Diehn, Pierre P. Massion. Mutational landscape of the bronchial epithelium of individuals at high risk for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2536.