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Whole-genome Characterization of Lung Adenocarcinomas Lacking Alterations in the RTK/RAS/RAF Pathway

Cell Reports. Volume 34; Issue 5, 2 February 2021 10.1016/j.celrep.2021.108707

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). To characterize the minority of LUADs lacking apparent alterations in this pathway, we used whole genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA). WGS analysis uncovered RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observed focal deletions targeting the promoter or transcription start site of STK11 (n=7) or KEAP1 (n=3), and promoter mutations associated with increased expression of ILF2 (n=6). We also identified complex structural variations associated with high level copy number amplifications. Moreover, an enrichment of focal deletions was 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.

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