Molecular subgroups of atypical teratoid rhabdoid tumours in children

An integrated genomic and clinicopathological analysis

Jonathon Torchia, Daniel Picard, Lucie Lafay-Cousin, Cynthia E. Hawkins, Seung Ki Kim, Louis Letourneau, Young Shin Ra, King Ching Ho, Tiffany Sin Yu Chan, Patrick Sin-Chan, Christopher P. Dunham, Stephen Yip, Ho keung Ng, Jian Qiang Lu, Steffen Albrecht, José Pimentel, Jennifer A. Chan, Gino R. Somers, Maria Zielenska, Claudia C. Faria & 52 others Lucia Roque, Berivan Baskin, Diane Birks, Nick Foreman, Douglas Strother, A. Klekner, M. Garami, P. Hauser, T. Hortobágyi, L. Bognár, Beverly Wilson, Juliette Hukin, Anne Sophie Carret, Timothy E. Van Meter, Hideo Nakamura, Helen Toledano, Iris Fried, Daniel Fults, Takafumi Wataya, Chris Fryer, David D. Eisenstat, Katrin Scheineman, Donna Johnston, Jean Michaud, Shayna Zelcer, Robert Hammond, David A. Ramsay, Adam J. Fleming, Rishi R. Lulla, Jason R. Fangusaro, Nongnuch Sirachainan, Noppadol Larbcharoensub, Suradej Hongeng, Muhammad Abrar Barakzai, Alexandre Montpetit, Derek Stephens, Richard G. Grundy, Ulrich Schüller, Theodore Nicolaides, Tarik Tihan, Joanna Phillips, Michael D. Taylor, James T. Rutka, Peter Dirks, Gary D. Bader, Monika Warmuth-Metz, Stefan Rutkowski, Torsten Pietsch, Alexander R. Judkins, Nada Jabado, Eric Bouffet, Annie Huang

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Background: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. Funding: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Original languageEnglish
Pages (from-to)569-582
Number of pages14
JournalThe Lancet Oncology
Volume16
Issue number5
DOIs
Publication statusPublished - 2015

Fingerprint

Neoplasms
Survival
Rhabdoid Tumor
Radiation
Typical Teratoid Rhabdoid Tumor
Atypical Teratoid Tumor
Drug Therapy
Combined Modality Therapy
Brain Neoplasms
Canada
Cohort Studies
Therapeutics
Genome
Brain
Research
Genes

ASJC Scopus subject areas

  • Oncology

Cite this

Torchia, J., Picard, D., Lafay-Cousin, L., Hawkins, C. E., Kim, S. K., Letourneau, L., ... Huang, A. (2015). Molecular subgroups of atypical teratoid rhabdoid tumours in children: An integrated genomic and clinicopathological analysis. The Lancet Oncology, 16(5), 569-582. https://doi.org/10.1016/S1470-2045(15)70114-2

Molecular subgroups of atypical teratoid rhabdoid tumours in children : An integrated genomic and clinicopathological analysis. / Torchia, Jonathon; Picard, Daniel; Lafay-Cousin, Lucie; Hawkins, Cynthia E.; Kim, Seung Ki; Letourneau, Louis; Ra, Young Shin; Ho, King Ching; Chan, Tiffany Sin Yu; Sin-Chan, Patrick; Dunham, Christopher P.; Yip, Stephen; Ng, Ho keung; Lu, Jian Qiang; Albrecht, Steffen; Pimentel, José; Chan, Jennifer A.; Somers, Gino R.; Zielenska, Maria; Faria, Claudia C.; Roque, Lucia; Baskin, Berivan; Birks, Diane; Foreman, Nick; Strother, Douglas; Klekner, A.; Garami, M.; Hauser, P.; Hortobágyi, T.; Bognár, L.; Wilson, Beverly; Hukin, Juliette; Carret, Anne Sophie; Van Meter, Timothy E.; Nakamura, Hideo; Toledano, Helen; Fried, Iris; Fults, Daniel; Wataya, Takafumi; Fryer, Chris; Eisenstat, David D.; Scheineman, Katrin; Johnston, Donna; Michaud, Jean; Zelcer, Shayna; Hammond, Robert; Ramsay, David A.; Fleming, Adam J.; Lulla, Rishi R.; Fangusaro, Jason R.; Sirachainan, Nongnuch; Larbcharoensub, Noppadol; Hongeng, Suradej; Barakzai, Muhammad Abrar; Montpetit, Alexandre; Stephens, Derek; Grundy, Richard G.; Schüller, Ulrich; Nicolaides, Theodore; Tihan, Tarik; Phillips, Joanna; Taylor, Michael D.; Rutka, James T.; Dirks, Peter; Bader, Gary D.; Warmuth-Metz, Monika; Rutkowski, Stefan; Pietsch, Torsten; Judkins, Alexander R.; Jabado, Nada; Bouffet, Eric; Huang, Annie.

In: The Lancet Oncology, Vol. 16, No. 5, 2015, p. 569-582.

Research output: Contribution to journalArticle

Torchia, J, Picard, D, Lafay-Cousin, L, Hawkins, CE, Kim, SK, Letourneau, L, Ra, YS, Ho, KC, Chan, TSY, Sin-Chan, P, Dunham, CP, Yip, S, Ng, HK, Lu, JQ, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Zielenska, M, Faria, CC, Roque, L, Baskin, B, Birks, D, Foreman, N, Strother, D, Klekner, A, Garami, M, Hauser, P, Hortobágyi, T, Bognár, L, Wilson, B, Hukin, J, Carret, AS, Van Meter, TE, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheineman, K, Johnston, D, Michaud, J, Zelcer, S, Hammond, R, Ramsay, DA, Fleming, AJ, Lulla, RR, Fangusaro, JR, Sirachainan, N, Larbcharoensub, N, Hongeng, S, Barakzai, MA, Montpetit, A, Stephens, D, Grundy, RG, Schüller, U, Nicolaides, T, Tihan, T, Phillips, J, Taylor, MD, Rutka, JT, Dirks, P, Bader, GD, Warmuth-Metz, M, Rutkowski, S, Pietsch, T, Judkins, AR, Jabado, N, Bouffet, E & Huang, A 2015, 'Molecular subgroups of atypical teratoid rhabdoid tumours in children: An integrated genomic and clinicopathological analysis', The Lancet Oncology, vol. 16, no. 5, pp. 569-582. https://doi.org/10.1016/S1470-2045(15)70114-2
Torchia, Jonathon ; Picard, Daniel ; Lafay-Cousin, Lucie ; Hawkins, Cynthia E. ; Kim, Seung Ki ; Letourneau, Louis ; Ra, Young Shin ; Ho, King Ching ; Chan, Tiffany Sin Yu ; Sin-Chan, Patrick ; Dunham, Christopher P. ; Yip, Stephen ; Ng, Ho keung ; Lu, Jian Qiang ; Albrecht, Steffen ; Pimentel, José ; Chan, Jennifer A. ; Somers, Gino R. ; Zielenska, Maria ; Faria, Claudia C. ; Roque, Lucia ; Baskin, Berivan ; Birks, Diane ; Foreman, Nick ; Strother, Douglas ; Klekner, A. ; Garami, M. ; Hauser, P. ; Hortobágyi, T. ; Bognár, L. ; Wilson, Beverly ; Hukin, Juliette ; Carret, Anne Sophie ; Van Meter, Timothy E. ; Nakamura, Hideo ; Toledano, Helen ; Fried, Iris ; Fults, Daniel ; Wataya, Takafumi ; Fryer, Chris ; Eisenstat, David D. ; Scheineman, Katrin ; Johnston, Donna ; Michaud, Jean ; Zelcer, Shayna ; Hammond, Robert ; Ramsay, David A. ; Fleming, Adam J. ; Lulla, Rishi R. ; Fangusaro, Jason R. ; Sirachainan, Nongnuch ; Larbcharoensub, Noppadol ; Hongeng, Suradej ; Barakzai, Muhammad Abrar ; Montpetit, Alexandre ; Stephens, Derek ; Grundy, Richard G. ; Schüller, Ulrich ; Nicolaides, Theodore ; Tihan, Tarik ; Phillips, Joanna ; Taylor, Michael D. ; Rutka, James T. ; Dirks, Peter ; Bader, Gary D. ; Warmuth-Metz, Monika ; Rutkowski, Stefan ; Pietsch, Torsten ; Judkins, Alexander R. ; Jabado, Nada ; Bouffet, Eric ; Huang, Annie. / Molecular subgroups of atypical teratoid rhabdoid tumours in children : An integrated genomic and clinicopathological analysis. In: The Lancet Oncology. 2015 ; Vol. 16, No. 5. pp. 569-582.
@article{06cf65c905954ee0ac1b9bc536a7c27b,
title = "Molecular subgroups of atypical teratoid rhabdoid tumours in children: An integrated genomic and clinicopathological analysis",
abstract = "Background: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35{\%}, 95{\%} CI 13-57, and 20{\%}, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34{\%}, 7-61, and 9{\%}, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95{\%} CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. Funding: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.",
author = "Jonathon Torchia and Daniel Picard and Lucie Lafay-Cousin and Hawkins, {Cynthia E.} and Kim, {Seung Ki} and Louis Letourneau and Ra, {Young Shin} and Ho, {King Ching} and Chan, {Tiffany Sin Yu} and Patrick Sin-Chan and Dunham, {Christopher P.} and Stephen Yip and Ng, {Ho keung} and Lu, {Jian Qiang} and Steffen Albrecht and Jos{\'e} Pimentel and Chan, {Jennifer A.} and Somers, {Gino R.} and Maria Zielenska and Faria, {Claudia C.} and Lucia Roque and Berivan Baskin and Diane Birks and Nick Foreman and Douglas Strother and A. Klekner and M. Garami and P. Hauser and T. Hortob{\'a}gyi and L. Bogn{\'a}r and Beverly Wilson and Juliette Hukin and Carret, {Anne Sophie} and {Van Meter}, {Timothy E.} and Hideo Nakamura and Helen Toledano and Iris Fried and Daniel Fults and Takafumi Wataya and Chris Fryer and Eisenstat, {David D.} and Katrin Scheineman and Donna Johnston and Jean Michaud and Shayna Zelcer and Robert Hammond and Ramsay, {David A.} and Fleming, {Adam J.} and Lulla, {Rishi R.} and Fangusaro, {Jason R.} and Nongnuch Sirachainan and Noppadol Larbcharoensub and Suradej Hongeng and Barakzai, {Muhammad Abrar} and Alexandre Montpetit and Derek Stephens and Grundy, {Richard G.} and Ulrich Sch{\"u}ller and Theodore Nicolaides and Tarik Tihan and Joanna Phillips and Taylor, {Michael D.} and Rutka, {James T.} and Peter Dirks and Bader, {Gary D.} and Monika Warmuth-Metz and Stefan Rutkowski and Torsten Pietsch and Judkins, {Alexander R.} and Nada Jabado and Eric Bouffet and Annie Huang",
year = "2015",
doi = "10.1016/S1470-2045(15)70114-2",
language = "English",
volume = "16",
pages = "569--582",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "5",

}

TY - JOUR

T1 - Molecular subgroups of atypical teratoid rhabdoid tumours in children

T2 - An integrated genomic and clinicopathological analysis

AU - Torchia, Jonathon

AU - Picard, Daniel

AU - Lafay-Cousin, Lucie

AU - Hawkins, Cynthia E.

AU - Kim, Seung Ki

AU - Letourneau, Louis

AU - Ra, Young Shin

AU - Ho, King Ching

AU - Chan, Tiffany Sin Yu

AU - Sin-Chan, Patrick

AU - Dunham, Christopher P.

AU - Yip, Stephen

AU - Ng, Ho keung

AU - Lu, Jian Qiang

AU - Albrecht, Steffen

AU - Pimentel, José

AU - Chan, Jennifer A.

AU - Somers, Gino R.

AU - Zielenska, Maria

AU - Faria, Claudia C.

AU - Roque, Lucia

AU - Baskin, Berivan

AU - Birks, Diane

AU - Foreman, Nick

AU - Strother, Douglas

AU - Klekner, A.

AU - Garami, M.

AU - Hauser, P.

AU - Hortobágyi, T.

AU - Bognár, L.

AU - Wilson, Beverly

AU - Hukin, Juliette

AU - Carret, Anne Sophie

AU - Van Meter, Timothy E.

AU - Nakamura, Hideo

AU - Toledano, Helen

AU - Fried, Iris

AU - Fults, Daniel

AU - Wataya, Takafumi

AU - Fryer, Chris

AU - Eisenstat, David D.

AU - Scheineman, Katrin

AU - Johnston, Donna

AU - Michaud, Jean

AU - Zelcer, Shayna

AU - Hammond, Robert

AU - Ramsay, David A.

AU - Fleming, Adam J.

AU - Lulla, Rishi R.

AU - Fangusaro, Jason R.

AU - Sirachainan, Nongnuch

AU - Larbcharoensub, Noppadol

AU - Hongeng, Suradej

AU - Barakzai, Muhammad Abrar

AU - Montpetit, Alexandre

AU - Stephens, Derek

AU - Grundy, Richard G.

AU - Schüller, Ulrich

AU - Nicolaides, Theodore

AU - Tihan, Tarik

AU - Phillips, Joanna

AU - Taylor, Michael D.

AU - Rutka, James T.

AU - Dirks, Peter

AU - Bader, Gary D.

AU - Warmuth-Metz, Monika

AU - Rutkowski, Stefan

AU - Pietsch, Torsten

AU - Judkins, Alexander R.

AU - Jabado, Nada

AU - Bouffet, Eric

AU - Huang, Annie

PY - 2015

Y1 - 2015

N2 - Background: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. Funding: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

AB - Background: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. Funding: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

UR - http://www.scopus.com/inward/record.url?scp=84933676892&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84933676892&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(15)70114-2

DO - 10.1016/S1470-2045(15)70114-2

M3 - Article

VL - 16

SP - 569

EP - 582

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 5

ER -