Abstract 728: Genomic alterations in lung adenocarcinoma precursor lesions

Abstract

Background: Adenocarcinoma of the lung is the most common type of non-small cell lung cancer and is the subtype found in approximately 50% of all lung cancer cases. Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are thought to be precursor lesions of invasive disease. It has been hypothesized that there is a step-wise progression to lung adenocarcinoma, but little is known about genomic alterations in these precursor lesions.Methods: Genomic analysis including whole genome and exome sequencing, and SNP array analysis were performed on 9 AIS and 18 MIA pathologically confirmed samples to identify single nucleotide variants (SNVs), structural variations and copy number variations. Mutation significance and signature analysis were determined by MutSig and NMF analyses. Altered pathways were determined by Ingenuity variant effect pathway analysis.Results: The tumor mutation burden (TMB) for AIS and MIA ranged from 0.8 to 23.1 mut/Mb with a median of 3.0mut/Mb and a mean of 5.1mut/Mb. Highly mutated genes identified in AIS and MIA were RPL10, NBPF1, KRAS, GPR52, CAMK2A, ATOX1, STK11, TP53, MET and EGFR. Genes with recurrent mutations included SPTA1, USH2A, CACNA1E, EGFR, KRAS, MUC16, MUC17, OTOG, RYR2, COL20A1, CSMD3, RFX6 and XIRP2, which implicated pathways involving the EGFR-KRAS-TP53-MAPK axis. Somatic mutations were characterized by a C>T, T>C transitions and C>A transversion signature. There were comparable structural variations in the AIS cases compared to MIA.Conclusion: In contrast to hypothesized models of tumor progression, AIS and MIA can harbor significant genomic alterations and tumor mutation burden, which suggests an intriguing concept of immunotherapeutic options for either treatment or chemoprevention. Deregulation of EGFR-KRAS-TP53-MAPK pathway indicates a role in early events of carcinogenesis.Citation Format: Michael K. Asiedu, Nanette R. Reed, Marie Christine Aubry, Anja C. Roden, Dennis A. Wigle. Genomic alterations in lung adenocarcinoma precursor lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 728.