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

TCGA Research Network

doi:10.1016/j.celrep.2021.108707

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

TCGA Research Network

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	American English
Article number	108707
Journal	Cell Reports
Volume	34
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2021.108707
State	Published - 2 Feb 2021

Bibliographical 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:
© 2021 The Authors

Keywords

TCGA
driver
genome analysis
lung adenocarcinoma
noncoding
oncogene
precision oncology
structural variation
tumor suppressor
whole genome sequencing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.108707

Cite this

@article{da2c993016eb49c3963a4d97d6162f31,

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 Berman, {Benjamin P.}",

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 = "American English",

volume = "34",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway

AU - TCGA Research Network

AU - Carrot-Zhang, Jian

AU - Yao, Xiaotong

AU - Devarakonda, Siddhartha

AU - Deshpande, Aditya

AU - Damrauer, Jeffrey S.

AU - Silva, Tiago Chedraoui

AU - Wong, Christopher K.

AU - Choi, Hyo Young

AU - Felau, Ina

AU - Robertson, A. Gordon

AU - Castro, Mauro A.A.

AU - Bao, Lisui

AU - Rheinbay, Esther

AU - Liu, Eric Minwei

AU - Trieu, Tuan

AU - Haan, David

AU - Yau, Christina

AU - Hinoue, Toshinori

AU - Liu, Yuexin

AU - Shapira, Ofer

AU - Kumar, Kiran

AU - Mungall, Karen L.

AU - Zhang, Hailei

AU - Lee, Jake June Koo

AU - Berger, Ashton

AU - Gao, Galen F.

AU - Zhitomirsky, Binyamin

AU - Liang, Wen Wei

AU - Zhou, Meng

AU - Moorthi, Sitapriya

AU - Berger, Alice H.

AU - Collisson, Eric A.

AU - Zody, Michael C.

AU - Ding, Li

AU - Cherniack, Andrew D.

AU - Getz, Gad

AU - Elemento, Olivier

AU - Benz, Christopher C.

AU - Stuart, Josh

AU - Zenklusen, J. C.

AU - Beroukhim, Rameen

AU - Chang, Jason C.

AU - Campbell, Joshua D.

AU - Hayes, D. Neil

AU - Yang, Lixing

AU - Laird, Peter W.

AU - Weinstein, John N.

AU - Kwiatkowski, David J.

AU - Tsao, Ming S.

AU - Berman, Benjamin P.

N1 - 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: © 2021 The Authors

PY - 2021/2/2

Y1 - 2021/2/2

N2 - 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.

AB - 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.

KW - TCGA

KW - driver

KW - genome analysis

KW - lung adenocarcinoma

KW - noncoding

KW - oncogene

KW - precision oncology

KW - structural variation

KW - tumor suppressor

KW - whole genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85100408037&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.108707

DO - 10.1016/j.celrep.2021.108707

M3 - Article

C2 - 33535033

AN - SCOPUS:85100408037

SN - 2211-1247

VL - 34

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 108707

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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