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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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