Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

Qingsong Gao; Wen Wei Liang; Steven M. Foltz; Gnanavel Mutharasu; Reyka G. Jayasinghe; Song Cao; Wen Wei Liao; Sheila M. Reynolds; Matthew A. Wyczalkowski; Lijun Yao; Lihua Yu; Sam Q. Sun; Samantha J. Caesar-Johnson; John A. Demchok; Ina Felau; Melpomeni Kasapi; Martin L. Ferguson; Carolyn M. Hutter; Heidi J. Sofia; Roy Tarnuzzer; Zhining Wang; Liming Yang; Jean C. Zenklusen; Jiashan (Julia) Zhang; Sudha Chudamani; Jia Liu; Laxmi Lolla; Rashi Naresh; Todd Pihl; Qiang Sun; Yunhu Wan; Ye Wu; Juok Cho; Timothy DeFreitas; Scott Frazer; Nils Gehlenborg; Gad Getz; David I. Heiman; Jaegil Kim; Michael S. Lawrence; Pei Lin; Sam Meier; Michael S. Noble; Gordon Saksena; Doug Voet; Hailei Zhang; Brady Bernard; Nyasha Chambwe; Varsha Dhankani; Ronald de Krijger

doi:10.1016/j.celrep.2018.03.050

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

Qingsong Gao, Wen Wei Liang, Steven M. Foltz, Gnanavel Mutharasu, Reyka G. Jayasinghe, Song Cao, Wen Wei Liao, Sheila M. Reynolds, Matthew A. Wyczalkowski, Lijun Yao, Lihua Yu, Sam Q. Sun, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy TarnuzzerZhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Ronald de Krijger, ,

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

2 Citations (Scopus)

Abstract

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability.

Original language	English
Pages (from-to)	227-238.e3
Journal	Cell Reports
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2018.03.050
Publication status	Published - 3 Apr 2018

Keywords

cancer
fusion
gene fusions
RNA
translocation

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10.1016/j.celrep.2018.03.050

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Gao, Q., Liang, W. W., Foltz, S. M., Mutharasu, G., Jayasinghe, R. G., Cao, S., Liao, W. W., Reynolds, S. M., Wyczalkowski, M. A., Yao, L., Yu, L., Sun, S. Q., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J. (2018). Driver Fusions and Their Implications in the Development and Treatment of Human Cancers. Cell Reports, 23(1), 227-238.e3. https://doi.org/10.1016/j.celrep.2018.03.050

@article{2b360b8d294c46d1a87586b8d8ec0419,

title = "Driver Fusions and Their Implications in the Development and Treatment of Human Cancers",

abstract = "Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability.",

keywords = "cancer, fusion, gene fusions, RNA, translocation",

author = "Qingsong Gao and Liang, {Wen Wei} and Foltz, {Steven M.} and Gnanavel Mutharasu and Jayasinghe, {Reyka G.} and Song Cao and Liao, {Wen Wei} and Reynolds, {Sheila M.} and Wyczalkowski, {Matthew A.} and Lijun Yao and Lihua Yu and Sun, {Sam Q.} and Caesar-Johnson, {Samantha J.} and Demchok, {John A.} and Ina Felau and Melpomeni Kasapi and Ferguson, {Martin L.} and Hutter, {Carolyn M.} and Sofia, {Heidi J.} and Roy Tarnuzzer and Zhining Wang and Liming Yang and Zenklusen, {Jean C.} and Zhang, {Jiashan (Julia)} and Sudha Chudamani and Jia Liu and Laxmi Lolla and Rashi Naresh and Todd Pihl and Qiang Sun and Yunhu Wan and Ye Wu and Juok Cho and Timothy DeFreitas and Scott Frazer and Nils Gehlenborg and Gad Getz and Heiman, {David I.} and Jaegil Kim and Lawrence, {Michael S.} and Pei Lin and Sam Meier and Noble, {Michael S.} and Gordon Saksena and Doug Voet and Hailei Zhang and Brady Bernard and Nyasha Chambwe and Varsha Dhankani and {de Krijger}, Ronald",

note = "Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae. Publisher Copyright: {\textcopyright} 2018 The Authors Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2018",

month = apr,

day = "3",

doi = "10.1016/j.celrep.2018.03.050",

language = "English",

volume = "23",

pages = "227--238.e3",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "1",

}

Gao, Q, Liang, WW, Foltz, SM, Mutharasu, G, Jayasinghe, RG, Cao, S, Liao, WW, Reynolds, SM, Wyczalkowski, MA, Yao, L, Yu, L, Sun, SQ, Caesar-Johnson, SJ, Demchok, JA, Felau, I, Kasapi, M, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Zhang, J, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Cho, J, DeFreitas, T, Frazer, S, Gehlenborg, N, Getz, G, Heiman, DI, Kim, J, Lawrence, MS, Lin, P, Meier, S, Noble, MS, Saksena, G, Voet, D, Zhang, H, Bernard, B, Chambwe, N, Dhankani, V, de Krijger, R 2018, 'Driver Fusions and Their Implications in the Development and Treatment of Human Cancers', Cell Reports, vol. 23, no. 1, pp. 227-238.e3. https://doi.org/10.1016/j.celrep.2018.03.050

TY - JOUR

T1 - Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

AU - Gao, Qingsong

AU - Liang, Wen Wei

AU - Foltz, Steven M.

AU - Mutharasu, Gnanavel

AU - Jayasinghe, Reyka G.

AU - Cao, Song

AU - Liao, Wen Wei

AU - Reynolds, Sheila M.

AU - Wyczalkowski, Matthew A.

AU - Yao, Lijun

AU - Yu, Lihua

AU - Sun, Sam Q.

AU - Caesar-Johnson, Samantha J.

AU - Demchok, John A.

AU - Felau, Ina

AU - Kasapi, Melpomeni

AU - Ferguson, Martin L.

AU - Hutter, Carolyn M.

AU - Sofia, Heidi J.

AU - Tarnuzzer, Roy

AU - Wang, Zhining

AU - Yang, Liming

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan (Julia)

AU - Chudamani, Sudha

AU - Liu, Jia

AU - Lolla, Laxmi

AU - Naresh, Rashi

AU - Pihl, Todd

AU - Sun, Qiang

AU - Wan, Yunhu

AU - Wu, Ye

AU - Cho, Juok

AU - DeFreitas, Timothy

AU - Frazer, Scott

AU - Gehlenborg, Nils

AU - Getz, Gad

AU - Heiman, David I.

AU - Kim, Jaegil

AU - Lawrence, Michael S.

AU - Lin, Pei

AU - Meier, Sam

AU - Noble, Michael S.

AU - Saksena, Gordon

AU - Voet, Doug

AU - Zhang, Hailei

AU - Bernard, Brady

AU - Chambwe, Nyasha

AU - Dhankani, Varsha

AU - de Krijger, Ronald

N1 - Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae. Publisher Copyright: © 2018 The Authors Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2018/4/3

Y1 - 2018/4/3

N2 - Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability.

AB - Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability.

KW - cancer

KW - fusion

KW - gene fusions

KW - RNA

KW - translocation

UR - http://www.scopus.com/inward/record.url?scp=85044744284&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.03.050

DO - 10.1016/j.celrep.2018.03.050

M3 - Article

AN - SCOPUS:85044744284

SN - 2211-1247

VL - 23

SP - 227-238.e3

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

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Keywords

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