Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Jonathon Torchia; Brian Golbourn; Shengrui Feng; King Ching Ho; Patrick Sin-Chan; Alexandre Vasiljevic; Joseph D. Norman; Paul Guilhamon; Livia Garzia; Natalia R. Agamez; Mei Lu; Tiffany S. Chan; Daniel Picard; Pasqualino de Antonellis; Dong Anh Khuong-Quang; Aline C. Planello; Constanze Zeller; Dalia Barsyte-Lovejoy; Lucie Lafay-Cousin; Louis Letourneau; Mathieu Bourgey; Man Yu; Deena M A Gendoo; Misko Dzamba; Mark Barszczyk; Tiago Medina; Alexandra N. Riemenschneider; A. Sorana Morrissy; Young Shin Ra; Vijay Ramaswamy; Marc Remke; Christopher P. Dunham; Stephen Yip; Ho keung Ng; Jian Qiang Lu; Vivek Mehta; Steffen Albrecht; Jose Pimentel; Jennifer A. Chan; Gino R. Somers; Claudia C. Faria; Lucia Roque; Maryam Fouladi; Lindsey M. Hoffman; Andrew S. Moore; Yin Wang; Seung Ah Choi; Jordan R. Hansford; Daniel Catchpoole; Diane K. Birks; Nicholas K. Foreman; Doug Strother; Almos Klekner; Laszló Bognár; Miklós Garami; Péter Hauser; Tibor Hortobágyi; Beverly Wilson; Juliette Hukin; Anne Sophie Carret; Timothy E. Van Meter; Eugene I. Hwang; Amar Gajjar; Shih Hwa Chiou; Hideo Nakamura; Helen Toledano; Iris Fried; Daniel Fults; Takafumi Wataya; Chris Fryer; David D. Eisenstat; Katrin Scheinemann; Adam J. Fleming; Donna L. Johnston; Jean Michaud; Shayna Zelcer; Robert Hammond; Samina Afzal; David A. Ramsay; Nongnuch Sirachainan; Suradej Hongeng; Noppadol Larbcharoensub; Richard G. Grundy; Rishi R. Lulla; Jason R. Fangusaro; Harriet Druker; Ute Bartels; Ronald Grant; David Malkin; C. Jane McGlade; Theodore Nicolaides; Tarik Tihan; Joanna Phillips; Jacek Majewski; Alexandre Montpetit; Guillaume Bourque; Gary D. Bader; Alyssa T. Reddy; G. Yancey Gillespie; Monika Warmuth-Metz; Stefan Rutkowski; Uri Tabori; Mathieu Lupien; Michael Brudno; Ulrich Schüller; Torsten Pietsch; Alexander R. Judkins; Cynthia E. Hawkins; Eric Bouffet; Seung Ki Kim; Peter B. Dirks; Michael D. Taylor; Anat Erdreich-Epstein; Cheryl H. Arrowsmith; Daniel D. De Carvalho; James T. Rutka; Nada Jabado; Annie Huang

doi:10.1016/j.ccell.2016.11.003

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Jonathon Torchia, Brian Golbourn, Shengrui Feng, King Ching Ho, Patrick Sin-Chan, Alexandre Vasiljevic, Joseph D. Norman, Paul Guilhamon, Livia Garzia, Natalia R. Agamez, Mei Lu, Tiffany S. Chan, Daniel Picard, Pasqualino de Antonellis, Dong Anh Khuong-Quang, Aline C. Planello, Constanze Zeller, Dalia Barsyte-Lovejoy, Lucie Lafay-Cousin, Louis LetourneauMathieu Bourgey, Man Yu, Deena M A Gendoo, Misko Dzamba, Mark Barszczyk, Tiago Medina, Alexandra N. Riemenschneider, A. Sorana Morrissy, Young Shin Ra, Vijay Ramaswamy, Marc Remke, Christopher P. Dunham, Stephen Yip, Ho keung Ng, Jian Qiang Lu, Vivek Mehta, Steffen Albrecht, Jose Pimentel, Jennifer A. Chan, Gino R. Somers, Claudia C. Faria, Lucia Roque, Maryam Fouladi, Lindsey M. Hoffman, Andrew S. Moore, Yin Wang, Seung Ah Choi, Jordan R. Hansford, Daniel Catchpoole, Diane K. Birks, Nicholas K. Foreman, Doug Strother, Almos Klekner, Laszló Bognár, Miklós Garami, Péter Hauser, Tibor Hortobágyi, Beverly Wilson, Juliette Hukin, Anne Sophie Carret, Timothy E. Van Meter, Eugene I. Hwang, Amar Gajjar, Shih Hwa Chiou, Hideo Nakamura, Helen Toledano, Iris Fried, Daniel Fults, Takafumi Wataya, Chris Fryer, David D. Eisenstat, Katrin Scheinemann, Adam J. Fleming, Donna L. Johnston, Jean Michaud, Shayna Zelcer, Robert Hammond, Samina Afzal, David A. Ramsay, Nongnuch Sirachainan, Suradej Hongeng, Noppadol Larbcharoensub, Richard G. Grundy, Rishi R. Lulla, Jason R. Fangusaro, Harriet Druker, Ute Bartels, Ronald Grant, David Malkin, C. Jane McGlade, Theodore Nicolaides, Tarik Tihan, Joanna Phillips, Jacek Majewski, Alexandre Montpetit, Guillaume Bourque, Gary D. Bader, Alyssa T. Reddy, G. Yancey Gillespie, Monika Warmuth-Metz, Stefan Rutkowski, Uri Tabori, Mathieu Lupien, Michael Brudno, Ulrich Schüller, Torsten Pietsch, Alexander R. Judkins, Cynthia E. Hawkins, Eric Bouffet, Seung Ki Kim, Peter B. Dirks, Michael D. Taylor, Anat Erdreich-Epstein, Cheryl H. Arrowsmith, Daniel D. De Carvalho^*, James T. Rutka, Nada Jabado, Annie Huang

^*Corresponding author for this work

Pediatrics

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

206 Scopus citations

Abstract

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Original language	English (US)
Pages (from-to)	891-908
Number of pages	18
Journal	Cancer cell
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2016.11.003
State	Published - Dec 12 2016

Funding

This work was supported by funds from Genome Canada, 110814 (A.H. and\u00A0N.J.), CCSRI #703279 (A.H. and D.D.C.), b.r.a.i.n.child, Mitchell Duckman, Tal Doron, and Suri Boon foundations (A.H. and J.T.R.) and C17 Childhood Cancer and Blood Disorders Research Network (L.L.C., E.B., A.H.). J.T. and P.S.C. are Ontario Graduate Scholars; D.G. and J.D.N. are, respectively, Brain Canada and CIHR Research Fellows. Technical support from V. Lau, A. Ma, and staff of the McGill University and G\u00E9nome Qu\u00E9bec Innovation Center, the Princess Margaret Genomics Center, the Center for Applied Genomics Toronto, the Rare Brain Tumor Consortium (http://www.rarebraintumorconsortium.ca), tumor banks of contributing centers (Table S8), and tissue contributions from Dr. A. Korshunov are gratefully acknowledged.

Keywords

ATRT
enhancer
epigenomics
genomics
rhabdoid tumors
subgroup-specific therapeutics

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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

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10.1016/j.ccell.2016.11.003

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Torchia, J., Golbourn, B., Feng, S., Ho, K. C., Sin-Chan, P., Vasiljevic, A., Norman, J. D., Guilhamon, P., Garzia, L., Agamez, N. R., Lu, M., Chan, T. S., Picard, D., de Antonellis, P., Khuong-Quang, D. A., Planello, A. C., Zeller, C., Barsyte-Lovejoy, D., Lafay-Cousin, L., ... Huang, A. (2016). Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors. Cancer cell, 30(6), 891-908. https://doi.org/10.1016/j.ccell.2016.11.003

@article{eaa18b9a7bf746dfb5a5536ff46d7bac,

title = "Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors",

abstract = "We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.",

keywords = "ATRT, enhancer, epigenomics, genomics, rhabdoid tumors, subgroup-specific therapeutics",

author = "Jonathon Torchia and Brian Golbourn and Shengrui Feng and Ho, {King Ching} and Patrick Sin-Chan and Alexandre Vasiljevic and Norman, {Joseph D.} and Paul Guilhamon and Livia Garzia and Agamez, {Natalia R.} and Mei Lu and Chan, {Tiffany S.} and Daniel Picard and {de Antonellis}, Pasqualino and Khuong-Quang, {Dong Anh} and Planello, {Aline C.} and Constanze Zeller and Dalia Barsyte-Lovejoy and Lucie Lafay-Cousin and Louis Letourneau and Mathieu Bourgey and Man Yu and Gendoo, {Deena M A} and Misko Dzamba and Mark Barszczyk and Tiago Medina and Riemenschneider, {Alexandra N.} and Morrissy, {A. Sorana} and Ra, {Young Shin} and Vijay Ramaswamy and Marc Remke and Dunham, {Christopher P.} and Stephen Yip and Ng, {Ho keung} and Lu, {Jian Qiang} and Vivek Mehta and Steffen Albrecht and Jose Pimentel and Chan, {Jennifer A.} and Somers, {Gino R.} and Faria, {Claudia C.} and Lucia Roque and Maryam Fouladi and Hoffman, {Lindsey M.} and Moore, {Andrew S.} and Yin Wang and Choi, {Seung Ah} and Hansford, {Jordan R.} and Daniel Catchpoole and Birks, {Diane K.} and Foreman, {Nicholas K.} and Doug Strother and Almos Klekner and Laszl{\'o} Bogn{\'a}r and Mikl{\'o}s Garami and P{\'e}ter Hauser and Tibor Hortob{\'a}gyi and Beverly Wilson and Juliette Hukin and Carret, {Anne Sophie} and {Van Meter}, {Timothy E.} and Hwang, {Eugene I.} and Amar Gajjar and Chiou, {Shih Hwa} and Hideo Nakamura and Helen Toledano and Iris Fried and Daniel Fults and Takafumi Wataya and Chris Fryer and Eisenstat, {David D.} and Katrin Scheinemann and Fleming, {Adam J.} and Johnston, {Donna L.} and Jean Michaud and Shayna Zelcer and Robert Hammond and Samina Afzal and Ramsay, {David A.} and Nongnuch Sirachainan and Suradej Hongeng and Noppadol Larbcharoensub and Grundy, {Richard G.} and Lulla, {Rishi R.} and Fangusaro, {Jason R.} and Harriet Druker and Ute Bartels and Ronald Grant and David Malkin and McGlade, {C. Jane} and Theodore Nicolaides and Tarik Tihan and Joanna Phillips and Jacek Majewski and Alexandre Montpetit and Guillaume Bourque and Bader, {Gary D.} and Reddy, {Alyssa T.} and Gillespie, {G. Yancey} and Monika Warmuth-Metz and Stefan Rutkowski and Uri Tabori and Mathieu Lupien and Michael Brudno and Ulrich Sch{\"u}ller and Torsten Pietsch and Judkins, {Alexander R.} and Hawkins, {Cynthia E.} and Eric Bouffet and Kim, {Seung Ki} and Dirks, {Peter B.} and Taylor, {Michael D.} and Anat Erdreich-Epstein and Arrowsmith, {Cheryl H.} and {De Carvalho}, {Daniel D.} and Rutka, {James T.} and Nada Jabado and Annie Huang",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = dec,

day = "12",

doi = "10.1016/j.ccell.2016.11.003",

language = "English (US)",

volume = "30",

pages = "891--908",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

Torchia, J, Golbourn, B, Feng, S, Ho, KC, Sin-Chan, P, Vasiljevic, A, Norman, JD, Guilhamon, P, Garzia, L, Agamez, NR, Lu, M, Chan, TS, Picard, D, de Antonellis, P, Khuong-Quang, DA, Planello, AC, Zeller, C, Barsyte-Lovejoy, D, Lafay-Cousin, L, Letourneau, L, Bourgey, M, Yu, M, Gendoo, DMA, Dzamba, M, Barszczyk, M, Medina, T, Riemenschneider, AN, Morrissy, AS, Ra, YS, Ramaswamy, V, Remke, M, Dunham, CP, Yip, S, Ng, HK, Lu, JQ, Mehta, V, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Faria, CC, Roque, L, Fouladi, M, Hoffman, LM, Moore, AS, Wang, Y, Choi, SA, Hansford, JR, Catchpoole, D, Birks, DK, Foreman, NK, Strother, D, Klekner, A, Bognár, L, Garami, M, Hauser, P, Hortobágyi, T, Wilson, B, Hukin, J, Carret, AS, Van Meter, TE, Hwang, EI, Gajjar, A, Chiou, SH, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheinemann, K, Fleming, AJ, Johnston, DL, Michaud, J, Zelcer, S, Hammond, R, Afzal, S, Ramsay, DA, Sirachainan, N, Hongeng, S, Larbcharoensub, N, Grundy, RG, Lulla, RR, Fangusaro, JR, Druker, H, Bartels, U, Grant, R, Malkin, D, McGlade, CJ, Nicolaides, T, Tihan, T, Phillips, J, Majewski, J, Montpetit, A, Bourque, G, Bader, GD, Reddy, AT, Gillespie, GY, Warmuth-Metz, M, Rutkowski, S, Tabori, U, Lupien, M, Brudno, M, Schüller, U, Pietsch, T, Judkins, AR, Hawkins, CE, Bouffet, E, Kim, SK, Dirks, PB, Taylor, MD, Erdreich-Epstein, A, Arrowsmith, CH, De Carvalho, DD, Rutka, JT, Jabado, N & Huang, A 2016, 'Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors', Cancer cell, vol. 30, no. 6, pp. 891-908. https://doi.org/10.1016/j.ccell.2016.11.003

TY - JOUR

T1 - Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

AU - Torchia, Jonathon

AU - Golbourn, Brian

AU - Feng, Shengrui

AU - Ho, King Ching

AU - Sin-Chan, Patrick

AU - Vasiljevic, Alexandre

AU - Norman, Joseph D.

AU - Guilhamon, Paul

AU - Garzia, Livia

AU - Agamez, Natalia R.

AU - Lu, Mei

AU - Chan, Tiffany S.

AU - Picard, Daniel

AU - de Antonellis, Pasqualino

AU - Khuong-Quang, Dong Anh

AU - Planello, Aline C.

AU - Zeller, Constanze

AU - Barsyte-Lovejoy, Dalia

AU - Lafay-Cousin, Lucie

AU - Letourneau, Louis

AU - Bourgey, Mathieu

AU - Yu, Man

AU - Gendoo, Deena M A

AU - Dzamba, Misko

AU - Barszczyk, Mark

AU - Medina, Tiago

AU - Riemenschneider, Alexandra N.

AU - Morrissy, A. Sorana

AU - Ra, Young Shin

AU - Ramaswamy, Vijay

AU - Remke, Marc

AU - Dunham, Christopher P.

AU - Yip, Stephen

AU - Ng, Ho keung

AU - Lu, Jian Qiang

AU - Mehta, Vivek

AU - Albrecht, Steffen

AU - Pimentel, Jose

AU - Chan, Jennifer A.

AU - Somers, Gino R.

AU - Faria, Claudia C.

AU - Roque, Lucia

AU - Fouladi, Maryam

AU - Hoffman, Lindsey M.

AU - Moore, Andrew S.

AU - Wang, Yin

AU - Choi, Seung Ah

AU - Hansford, Jordan R.

AU - Catchpoole, Daniel

AU - Birks, Diane K.

AU - Foreman, Nicholas K.

AU - Strother, Doug

AU - Klekner, Almos

AU - Bognár, Laszló

AU - Garami, Miklós

AU - Hauser, Péter

AU - Hortobágyi, Tibor

AU - Wilson, Beverly

AU - Hukin, Juliette

AU - Carret, Anne Sophie

AU - Van Meter, Timothy E.

AU - Hwang, Eugene I.

AU - Gajjar, Amar

AU - Chiou, Shih Hwa

AU - Nakamura, Hideo

AU - Toledano, Helen

AU - Fried, Iris

AU - Fults, Daniel

AU - Wataya, Takafumi

AU - Fryer, Chris

AU - Eisenstat, David D.

AU - Scheinemann, Katrin

AU - Fleming, Adam J.

AU - Johnston, Donna L.

AU - Michaud, Jean

AU - Zelcer, Shayna

AU - Hammond, Robert

AU - Afzal, Samina

AU - Ramsay, David A.

AU - Sirachainan, Nongnuch

AU - Hongeng, Suradej

AU - Larbcharoensub, Noppadol

AU - Grundy, Richard G.

AU - Lulla, Rishi R.

AU - Fangusaro, Jason R.

AU - Druker, Harriet

AU - Bartels, Ute

AU - Grant, Ronald

AU - Malkin, David

AU - McGlade, C. Jane

AU - Nicolaides, Theodore

AU - Tihan, Tarik

AU - Phillips, Joanna

AU - Majewski, Jacek

AU - Montpetit, Alexandre

AU - Bourque, Guillaume

AU - Bader, Gary D.

AU - Reddy, Alyssa T.

AU - Gillespie, G. Yancey

AU - Warmuth-Metz, Monika

AU - Rutkowski, Stefan

AU - Tabori, Uri

AU - Lupien, Mathieu

AU - Brudno, Michael

AU - Schüller, Ulrich

AU - Pietsch, Torsten

AU - Judkins, Alexander R.

AU - Hawkins, Cynthia E.

AU - Bouffet, Eric

AU - Kim, Seung Ki

AU - Dirks, Peter B.

AU - Taylor, Michael D.

AU - Erdreich-Epstein, Anat

AU - Arrowsmith, Cheryl H.

AU - De Carvalho, Daniel D.

AU - Rutka, James T.

AU - Jabado, Nada

AU - Huang, Annie

PY - 2016/12/12

Y1 - 2016/12/12

N2 - We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

AB - We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

KW - ATRT

KW - enhancer

KW - epigenomics

KW - genomics

KW - rhabdoid tumors

KW - subgroup-specific therapeutics

UR - http://www.scopus.com/inward/record.url?scp=85004009880&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85004009880&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.11.003

DO - 10.1016/j.ccell.2016.11.003

M3 - Article

C2 - 27960086

AN - SCOPUS:85004009880

SN - 1535-6108

VL - 30

SP - 891

EP - 908

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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