Abstract 2055: Prevalent focal amplification of oncogene in lung adenocarcinomas without canonical driver alterations

Abstract

Abstract Lung adenocarcinoma (LADC) is the most common type of lung cancer and a leading cause of death worldwide. Typical oncogenes that drive LADCs when mutated (referred to as canonical drivers) include EGFR (30-60%), KRAS (10-30%), and fusion oncogenes (~10%) involving ALK, RET, and ROS1. However, approximately 30% of lung adenocarcinomas lack canonical drivers, implying unseen kinds of genomic alterations. Here, we explore alterations beyond the scope of canonical drivers in LADCs (referred to as non-canonical drivers) using large-scale whole-genome sequencing (WGS) of LADCs. We gathered total 183 WGS of LADCs, 138 of which were from our previous study (Lee et al. Cell. 2019) and 45 were newly sequenced from surgically resected LADCs. For raw data processing, we used a standard WGS analysis pipeline from read mapping to variant calling. Variant filtering and downstream analyses were performed using in-house scripts. Genomic variants analyzed in this study include single-base substitution (SBS), indel, structural variation (SV), and copy number variation (CNV). As a result, we found that 53 cases (29%) had no canonical drivers (ND group). Intriguingly, LADCs without canonical drivers had a contrasting genomic landscape compared to LADCs with canonical drivers (CD group). First, the point-mutation burden was ~3-fold higher in the ND group than in the CD group (52,500 vs. 17,900 for SNVs, p<0.001). Mutational signature analysis revealed that these additional mutations are attributable mainly to tobacco smoking (by mutational signature SBS4) and APOBEC-mediated mutagenesis (SBS12 and SBS13) and that they are more enriched in the ND group (4,800 vs 2,600, p=0.03). Second, the ND group harbored more frequent focal amplifications. Recurrently amplified genes include TERT, IL7R, NKX2-1, CCND1, CCND3, CCNE1, and EGFR. The pattern of SVs suggest that the amplifications occurred through the formation of extra-chromosomal DNA involving multiple chromosomes or following chromothripsis. Overall, this study broadens our understanding of non-canonical drivers of LADCs. Similar analyses of thousands of cancers with clinical information of the patient will likely yield the functional impact of these driver mutations and may offer more opportunities for LADC treatment in the future. Citation Format: Seongyeol Park, Joonoh Lim, Kijong Yi, Boram Yi, Ryul Kim, Jaemo Koo, Kwon Joong Na, Samina Park, In Kyu Park, Chang Hyun Kang, Jeong Seok Lee, Young Seok Ju, Young Tae Kim. Prevalent focal amplification of oncogene in lung adenocarcinomas without canonical driver alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2055.