Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway
Jian Carrot‐Zhang, Xiaotong Yao, Siddhartha Devarakonda, Aditya Deshpande, Jeffrey S. Damrauer, Tiago C. Silva, Christopher K. Wong, Hyo Young Choi, Ina Felau, A. Gordon Robertson, Mauro A. A. Castro, Lisui Bao, Esther Rheinbay, Eric Minwei Liu, Tuan Trieu, David Haan, Christina Yau, Toshinori Hinoue, Yuexin Liu, Ofer Shapira, Kiran Kumar, Karen Mungall, Hailei Zhang, Jake June-Koo Lee, Ashton C. Berger, Galen F. Gao, Binyamin Zhitomirsky, Wen-Wei Liang, Meng Zhou, Sitapriya Moorthi, Alice H. Berger, Eric A. Collisson, Michael C. Zody, Li Ding, Andrew D. Cherniack, Gad Getz, Olivier Elemento, Christopher C. Benz, Joshua M. Stuart, Jean C. Zenklusen, Rameen Beroukhim, Jason C. Chang, Joshua D. Campbell, D. Neil Hayes, Lixing Yang, Peter W. Laird, John N. Weinstein, David J. Kwiatkowski, Ming‐Sound Tsao, William D. Travis, Ekta Khurana, Benjamin P. Berman, Katherine A. Hoadley, Nicolas Robine, Kanika Arora, Minita Shah, Jennifer Shelton, Reanne Bowlby, Verena Friedl, Mary J. Goldman, Brian Craft, David I. Heiman, Iman Hajirasouliha, Camir Ricketts, Pavana Anur, Kami Chiotti, Rory Johnson, John A. Demchok, Martin L. Ferguson, Anab Kemal, Roy Tarnuzzer, Zhining Wang, Liming Yang, Paul T. Spellman, Benjamin J. Raphael, Rehan Akbani, Jingchun Zhu, Steven J.M. Jones, Hui Shen, Matthew Meyerson, Ramaswamy Govindan, Marcin Imieliński
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.