P2.03-10 Comprehensive Molecular Profiling and Comparison of Common and Rarer Subtypes of Lung Cancer

Abstract

Genomic profiling of tumours has become a crucial component of precision cancer medicine. In order to comprehensively characterize molecular alterations in different lung cancer subtypes, we analysed a total number of 327 samples by using Whole-Exome Sequencing (WES) and SNP genotyping arrays. Additionally, we used Targeted Capture Sequencing (TCS) for scanning a selected panel of genes (n=52) at high sequencing depth. We WES (McGill University Innovation Centre in Montreal) 153 paired tumour-normal samples, with a further 174 paired tumour-normal samples undergoing TCS. Sequencing data were processed and mutations identified using BWA (v.0.7.15), Picard (v.2.17.11), GATK (v.3.7), VarScan (v.2.4.2) and VEP (v. 92) softwares. Illumina OmniExpressExome (v1.6) arrays were used for genotyping all samples and copy number alterations (CNAs) were identified using ASCAT (v.2.5.2), DNACopy (v.1.56.0) and GISTIC (v.2.0) softwares. The analysed samples had a tumour content varying from 20 to 90%. The age range of patients was between 28 to 89 years. Out of 159 lung cancer patients, 89 patients had lung adenocarcinoma (LUAD), 36 squamous cell carcinoma (LUSC) and 34 lung neuroendocrine (NET), of which 22 were subclassified as lung carcinoid (LC), 6 small cell carcinoma (LSCLC), 5 large cell carcinoma (LCNEC) and 1 combined NET subtype. TP53 appeared as the most mutated gene in LUSCs (82%), non-carcinoid NETs (58%) and LUADs (47%), but not in the LC subtype, while the chromatin remodelling gene ARID1A was altered across all subtypes (9%). Other mutated genes in LUAD were KRAS (31%), STK11 (22%), RBM10 (15%), EGFR (14%) and KEAP1 (14%); in LUSC were PTEN (26%), CDKN2A (21%), KEAP1 (21%) and NF1 (15%); in NET, non-carcinoid top mutated genes included RB1 (42%), ENPP2 (33%), ERBB4 and STK11 (17% for each), while ARID1A and ACKR3 were each present in 9.5 % of LC. In LUADs, mutations in EGFR and KRAS appeared as mutually-exclusive (P=0.007), while gene pairs NFE2L2 - AKT1 (P=0.012) and STK11- ALK (P=0.029) were co-mutated in LUAD and LUSC, respectively. Deletions in exons 19 and 20 of EGFR correlated with longer survival time compared to patients with wild-type EGFR (P=0.058). In NET, patients with mutated RB1 showed lower survival time compared to patients with wild-type RB1 (P=0.022). Examination of CNAs showed TERT amplifications (5p15.33 cytoband) were commonly found at high frequencies across all subtypes, especially in non-carcinoid NET (71.4%). Other recurrent CNAs included amplifications in MYC in 37% of LUAD and 40% of LUSC, and in EGFR in 33% of LUAD and 14% of LUSC. Deletions in the CDKN2A locus were seen at frequencies of 31% and 28% in LUAD and LUSC, respectively. LC patients showed longer survival time compared to other tumours (P=0.015). COSMIC mutational signatures 18 (of unknown aetiology) and 24 (associated with exposure to aflatoxin) were exclusively found in LC. The results confirm that lung cancer is a group of heterogenous diseases. In addition to the known effects of EFGR mutations, possible therapeutic avenues could be suggested for TERT amplifications, for which nucleoside analogues have shown to promote cancer cell death or EZH2 inhibitors for ARID1A-mutated cancers.