Abstract 5895: Whole-genome characterization of lung adenocarcinomas lacking alterations in RTK/RAS/RAF/MAPK pathway
Authors: Carrot-Zhang Jian , Devarakonda Siddhartha , Robine Nicolas , Yao Xiaotong , Silva Tiago C. , Damrauer Jeff , Deshpande Aditya , Tsao Ming-Sound , Yao Christina , Wong Chris , Bao Lisui , Choi Hyo Young , Felau Ina , Zenklusen Jean C. , Robertson Gordon , Trieua Tuan , Liang Wei-Wei , Zhou Meng , Rheinbay Esther , Hayes Neil , Khurana Ekta , Ding Li , Laird Peter , Elemento Olivier , Weinstein John , Kwiatkowski David , Benz Chris , Stuart Josh , Yang Lixing , Castro Mauro , Travis William , Hoadley Katherine , Berman Ben ,   TCGA Analysis Network, Meyerson Matthew , Govindan Ramaswamy , Imielinski Marcin 
Published: September 2020

Abstract
Lung adenocarcinomas (LUAD) are typically characterized by genetic activation of the receptor tyrosine kinase (RTK)/RAS/RAF/MAP kinase (MAPK) pathway. A minority of LUAD cases (20-25%) lack apparent genetic alterations in this pathway, and thus are ineligible for most targeted therapies. These candidate “oncogene negative” LUADs may harbor novel classes of oncogenic drivers or represent a biologically distinct class of tumors. To characterize the genomic landscape of oncogene-negative LUADs, we nominated 98 cases that were found to lack an activating RTK/RAS/RAF/MAPK pathway alteration in a TCGA study utilizing whole exome sequencing, microarray, and transcriptome data. We profiled these tumors with high-depth whole genome sequencing (WGS), with the goal of identifying noncoding and structural variant driver DNA alterations in both known and novel loci. Of the 98 cases, 20 harbored somatic KRAS mutations that had been missed in the prior WES and transcriptome studies because of insufficient coverage, including 8 cases with the recently targetable p.G12C mutation. 16 samples harbored oncogenic or loss-of-function structural variants in FGFR1, MAPK1, EGFR, NF1, RASA1, ARAF, NTRK2 and NRG1. 5 other samples with SNV or indels in EGFR, ERBB2 and SOS1 were reclassified as oncogene positive. Thus via comprehensive genomic analysis, we confirmed that 57 of the 98 WGS cases did not harbor any detectable alterations in genes encoding any known RTK/RAS/RAF/MAPK members, representing 13% cases chosen as “lung adenocarcinomas” for the TCGA study. Among the 57 confirmed oncogene-negative LUADs, we identified focal deletions targeting the promoter and transcription start site of tumor suppressor genes STK11, KEAP1 and SMARCA4 in 10 samples. Expression and methylation profiling suggested an enrichment of the TP53-deficient phenotype, including cell cycle and FOXM1 deregulation, among the oncogene-negative samples. Moreover, novel promoter mutations associated with increased expression were identified in ILF2, which regulates DNA damage response pathways. Finally, a subset of confirmed oncogene-negative LUADs harbored increased expression of neuroendocrine markers, suggesting that these oncogene-negative samples may either be mis-diagnosed as LUAD or represent LUAD with mixed features of other subtypes of lung cancer; indeed, 14 of the 57 confirmed oncogene-negative cases show histological features of large cell neuroendocrine lung carcinoma. This would suggest that 10% of the cases in this study are both lung adenocarcinoma and “oncogene-negative” to date. Our results provide some of the first comprehensive genomic characterization of oncogene-negative LUADs, implicating TP53 and structural variants in the pathogenesis of this common and difficult to treat entity.
Citation Format: Jian Carrot-Zhang, Siddhartha Devarakonda, Nicolas Robine, Xiaotong Yao, Tiago C. Silva, Jeff Damrauer, Aditya Deshpande, Ming-Sound Tsao, Christina Yao, Chris Wong, Lisui Bao, Hyo Young Choi, Ina Felau, Jean C. Zenklusen, Gordon Robertson, Tuan Trieua, Wei-Wei Liang, Meng Zhou, Esther Rheinbay, Neil Hayes, Ekta Khurana, Li Ding, Peter Laird, Olivier Elemento, John Weinstein, David Kwiatkowski, Chris Benz, Josh Stuart, Lixing Yang, Mauro Castro, William Travis, Katherine Hoadley, Ben Berman, TCGA Analysis Network, Matthew Meyerson, Ramaswamy Govindan, Marcin Imielinski. Whole-genome characterization of lung adenocarcinomas lacking alterations in RTK/RAS/RAF/MAPK pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5895.