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

  • Author(s): Carrot-Zhang, Jian
  • Yao, Xiaotong
  • Devarakonda, Siddhartha
  • Deshpande, Aditya
  • Damrauer, Jeffrey S
  • Silva, Tiago Chedraoui
  • Wong, Christopher K
  • Choi, Hyo Young
  • Felau, Ina
  • Robertson, A Gordon
  • Castro, Mauro AA
  • Bao, Lisui
  • Rheinbay, Esther
  • Liu, Eric Minwei
  • Trieu, Tuan
  • Haan, David
  • Yau, Christina
  • Hinoue, Toshinori
  • Liu, Yuexin
  • Shapira, Ofer
  • Kumar, Kiran
  • Mungall, Karen L
  • Zhang, Hailei
  • Lee, Jake June-Koo
  • Berger, Ashton
  • Gao, Galen F
  • Zhitomirsky, Binyamin
  • Liang, Wen-Wei
  • Zhou, Meng
  • Moorthi, Sitapriya
  • Berger, Alice H
  • Collisson, Eric A
  • Zody, Michael C
  • Ding, Li
  • Cherniack, Andrew D
  • Getz, Gad
  • Elemento, Olivier
  • Benz, Christopher C
  • Stuart, Josh
  • Zenklusen, JC
  • Beroukhim, Rameen
  • Chang, Jason C
  • Campbell, Joshua D
  • Hayes, D Neil
  • Yang, Lixing
  • Laird, Peter W
  • Weinstein, John N
  • Kwiatkowski, David J
  • Tsao, Ming S
  • Travis, William D
  • Khurana, Ekta
  • Berman, Benjamin P
  • Hoadley, Katherine A
  • Robine, Nicolas
  • TCGA Research Network
  • Meyerson, Matthew
  • Govindan, Ramaswamy
  • Imielinski, Marcin
  • et al.

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.

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