Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
Competing Interests: Declaration of interests M.M. is listed as the inventor on the patent for the EGFR mutation analysis for lung cancer diagnosis licensed to LabCorp; holds research support from Bayer, Janssen, and Ono; and serves as scientific advisory board chair for OrigiMed. P.W.L. serves on the scientific advisory boards of AnchorDx and Progenity. D.J.K. has research support from Revolution Medicines and Genentech and is a consultant to AADi.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)