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

Authors: Carrot-Zhang, J.; Yao, X.; Devarakonda, S.; Deshpande, A.; Damrauer, J. S.; Silva, T. C.; Wong, C. K.; Choi, H. Y.; Felau, I.; Robertson, A. G.; Castro, M. A. A.; Bao, L.; Rheinbay, E.; Liu, E. M.; Trieu, T.; Haan, D.; Yau, C.; Hinoue, T.; Liu, Y.; Shapira, O.; Kumar, K.; Mungall, K. L.; Zhang, H.; Lee, J. J. K.; Berger, A.; Gao, G. F.; Zhitomirsky, B.; Liang, W. W.; Zhou, M.; Moorthi, S.; Berger, A. H.; Collisson, E. A.; Zody, M. C.; Ding, L.; Cherniack, A. D.; Getz, G.; Elemento, O.; Benz, C. C.; Stuart, J.; Zenklusen, J. C.; Beroukhim, R.; Chang, J. C.; Campbell, J. D.; Hayes, D. N.; Yang, L.; Laird, P. W.; Weinstein, J. N.; Kwiatkowski, D. J.; Tsao, M. S.; Travis, W. D.; Khurana, E.; Berman, B. P.; Hoadley, K. A.; Robine, N.; TCGA Research Network; Meyerson, M.; Govindan, R.; Imielinski, M.
Article Title: Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway
Abstract: 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. © 2021 The Authors Carrot-Zhang et al. perform whole-genome characterization of lung adenocarcinomas (LUADs) lacking RTK/RAS/RAF pathway alterations (RPAs) and identify mutations or structural variants in both coding and non-coding spaces that define a unique entity of RPA(−) LUADs and potentially explain the underlying biology of this disease. © 2021 The Authors
Keywords: genome analysis; oncogene; lung adenocarcinoma; tumor suppressor; tcga; structural variation; whole genome sequencing; driver; precision oncology; noncoding
Journal Title: Cell Reports
Volume: 34
Issue: 5
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2021-02-02
Start Page: 108707
Language: English
DOI: 10.1016/j.celrep.2021.108707
PUBMED: 33535033
PROVIDER: scopus
PMCID: PMC8009291
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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MSK Authors
  1. William D Travis
    698 Travis
  2. Jason Chih-Peng Chang
    98 Chang