P1.03-50 Type- and Stage-Specific Genomic Profiles in East Asian Lung Cancer Patients with No TKI-Related Driver Gene Mutations

Abstract

It is widely accepted that the development of advanced lung cancer or distant metastases rely on driver gene mutations, but the carcinogenesis of lung cancers without key driver gene mutations has not been fully understood. The genomic landscape of lung adenocarcinoma (LADC), lung squamous cell carcinoma (LUSC) and small cell lung cancer (SCLC) without TKI-related driver gene mutations in East Asian has not been well investigated. Systematic study of these subtypes may identify biomarkers to distinguish different types and find novel tractable targets for therapy. We have therefore studied the genomic profiles of these types of lung cancers to identify type-specific and stage-specific gene mutations. 32 LADC patients, 43 LUSC patients and 26 SCLC patients with no TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET, HER2) mutations were included in this study. Genomic profiles were determined with lung cancer tissue by whole-exome sequencing (WES). Sequencing data were analyzed with R packages and statistics was performed with SPSS 20. In 101 patients enrolled, TP53, TTN, MUC4, ZFHX4 and CSMD3 mutations were commonly detected in all 3 types of lung cancer, and TP53 was the commonest mutated gene. Markedly, KRAS mutations were found only in LADC, and CSMD1 mutations were more frequent in LUSC, whereas RB1 mutations were observed exclusively in SCLC. LRP1B and RYR2 mutations were found more frequently at late stages. Copy number variations (CNV) in TERT, RICTOR and FGFR1 were seen in all 3 subtypes. The PIK3CA copy number gain was commonly seen in LUSC and SCLC other than that in LADC. In contrast, the CDKN2A copy-number loss was found in LADC and LUSC, but not in SCLC. The PTEN copy number loss was only identified in LUSC. No significant differences in TMB were observed among these 3 subtypes of lung cancer. However, statistical significance in TMB was attained between non-small cell lung cancer (NSCLC) and SCLC (P=0.022) in stage Ⅳ patients when the cut-off of TMB was set to 4.5 muts/MB. Results from this genomic study confirmed the mutual and exclusive gene variations (including gene mutations and copy number variations) in 3 subtypes of lung cancer. It showed that gene variations were associated with lung cancer subtypes in patients with no TKI-related driver gene mutations. These findings might detected subtype-specific biomarkers to assist histological-based diagnosis, and help to identify potential type-specific targets for lung cancer therapy.