@article{bc167d93ffd9425296d77fa3ed9171ec,
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.",
keywords = "TCGA, driver, genome analysis, lung adenocarcinoma, noncoding, oncogene, precision oncology, structural variation, tumor suppressor, whole genome sequencing",
author = "{TCGA Research Network} and Jian Carrot-Zhang and Xiaotong Yao and Siddhartha Devarakonda and Aditya Deshpande and Damrauer, {Jeffrey S.} and Silva, {Tiago Chedraoui} and Wong, {Christopher K.} and Choi, {Hyo Young} and Ina Felau and Robertson, {A. Gordon} and Castro, {Mauro A.A.} and Lisui Bao and Esther Rheinbay and Liu, {Eric Minwei} and Tuan Trieu and David Haan and Christina Yau and Toshinori Hinoue and Yuexin Liu and Ofer Shapira and Kiran Kumar and Mungall, {Karen L.} and Hailei Zhang and Lee, {Jake June Koo} and Ashton Berger and Gao, {Galen F.} and Binyamin Zhitomirsky and Liang, {Wen Wei} and Meng Zhou and Sitapriya Moorthi and Berger, {Alice H.} and Collisson, {Eric A.} and Zody, {Michael C.} and Li Ding and Cherniack, {Andrew D.} and Gad Getz and Olivier Elemento and Benz, {Christopher C.} and Josh Stuart and Zenklusen, {J. C.} and Rameen Beroukhim and Chang, {Jason C.} and Campbell, {Joshua D.} and Hayes, {D. Neil} and Lixing Yang and Laird, {Peter W.} and Weinstein, {John N.} and Kwiatkowski, {David J.} and Tsao, {Ming S.} and Spellman, {Paul T.}",
note = "Funding Information: We thank the US National Cancer Institute for funding through U24 grants CA210999, CA210974, CA211006, CA210949, CA210978, CA210952, CA210989, CA210957, CA210990, CA211000, CA210950, CA210969, and CA210988. J.C.-Z. holds a CIHR Banting fellowship. M.I. X.Y. and A.D. were also partially supported by M.I.'s Burroughs Wellcome Fund Career Award for Medical Scientists and startup funds from the Weill Cornell Medicine Department of Pathology and Laboratory Medicine. We are grateful for advice from numerous colleagues at our respective institutions, TCGA and GDAN collaborators, and the GDC technical support team. J.C.-Z. X.Y. S.D. and N.R. are the data/analysis/manuscript coordinators of this project. J.C.-Z. X.Y. H.Y.C. T.T. H.Z. M.C.Z. N.R. and M.I. generated raw calls; J.C.-Z. X.Y. A.D. J.S.D. T.C.S. C.K.W. H.Y.C. A.G.R. M.A.A.C. L.B. E.R. E.M.L. T.T. D.H. C.Y. T.H. Y.L. O.S. K.K. K.L.M. H.Z. J.J.-K.L. A.B. G.F.G. B.Z. W.-W.L. and M.I. performed the analyses; S.D. S.M. A.H.B. E.A.C. J.N.W. and D.J.K. contributed to the data interpretation; S.D. E.A.C. J.C.C. M.S.T. W.D.T. and R.G. provided the clinical interpretation; I.F. and J.C.Z. provided project administration; L.D. A.D.C. G.G. R.B. O.E. C.C.B. J.S. J.D.C. D.N.H. L.Y. P.W.L. J.N.W. D.J.K. E.K. B.P.B. K.A.H. N.R. M.M. and M.I. supervised the analyses; J.C.-Z. X.Y. S.D. J.N.W. D.J.K. M.M. R.G. and M.I. wrote the manuscript; all of the authors edited or reviewed the manuscript; M.M. R.G. and M.I. are the co-chairs of this project. M.M. is listed as the inventor on the patent for the EGFR mutation analysis for lung cancer diagnosis licensed to LabCorp; holds research support from Bayer, Janssen, and Ono; and serves as scientific advisory board chair for OrigiMed. P.W.L. serves on the scientific advisory boards of AnchorDx and Progenity. D.J.K. has research support from Revolution Medicines and Genentech and is a consultant to AADi. Funding Information: We thank the US National Cancer Institute for funding through U24 grants CA210999 , CA210974 , CA211006 , CA210949 , CA210978 , CA210952 , CA210989 , CA210957 , CA210990 , CA211000 , CA210950 , CA210969 , and CA210988. J.C.-Z. holds a CIHR Banting fellowship . M.I., X.Y., and A.D. were also partially supported by M.I.'s Burroughs Wellcome Fund Career Award for Medical Scientists and startup funds from the Weill Cornell Medicine Department of Pathology and Laboratory Medicine. We are grateful for advice from numerous colleagues at our respective institutions, TCGA and GDAN collaborators, and the GDC technical support team. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = feb,
day = "2",
doi = "10.1016/j.celrep.2021.108707",
language = "English (US)",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}