Intertumoral Heterogeneity within Medulloblastoma Subgroups

Florence M.G. Cavalli, Marc Remke, Ladislav Rampasek, John Peacock, David J.H. Shih, Betty Luu, Livia Garzia, Jonathon Torchia, Carolina Nor, A. Sorana Morrissy, Sameer Agnihotri, Yuan Yao Thompson, Claudia M. Kuzan-Fischer, Hamza Farooq, Keren Isaev, Craig Daniels, Byung Kyu Cho, Seung Ki Kim, Kyu Chang Wang, Ji Yeoun LeeWieslawa A. Grajkowska, Marta Perek-Polnik, Alexandre Vasiljevic, Cecile Faure-Conter, Anne Jouvet, Caterina Giannini, Amulya A. Nageswara Rao, Kay Ka Wai Li, Ho Keung Ng, Charles G Eberhart, Ian F. Pollack, Ronald L. Hamilton, G. Yancey Gillespie, James M. Olson, Sarah Leary, William A. Weiss, Boleslaw Lach, Lola B. Chambless, Reid C. Thompson, Michael K. Cooper, Rajeev Vibhakar, Peter Hauser, Marie Lise C. van Veelen, Johan M. Kros, Pim J. French, Young Shin Ra, Toshihiro Kumabe, Enrique López-Aguilar, Karel Zitterbart, Jaroslav Sterba, Gaetano Finocchiaro, Maura Massimino, Erwin G. Van Meir, Satoru Osuka, Tomoko Shofuda, Almos Klekner, Massimo Zollo, Jeffrey R. Leonard, Joshua B. Rubin, Nada Jabado, Steffen Albrecht, Jaume Mora, Timothy E. Van Meter, Shin Jung, Andrew S. Moore, Andrew R. Hallahan, Jennifer A. Chan, Daniela P.C. Tirapelli, Carlos G. Carlotti, Maryam Fouladi, José Pimentel, Claudia C. Faria, Ali G. Saad, Luca Massimi, Linda M. Liau, Helen Wheeler, Hideo Nakamura, Samer K. Elbabaa, Mario Perezpeña-Diazconti, Fernando Chico Ponce de León, Shenandoah Robinson, Michal Zapotocky, Alvaro Lassaletta, Annie Huang, Cynthia E. Hawkins, Uri Tabori, Eric Bouffet, Ute Bartels, Peter B. Dirks, James T. Rutka, Gary D. Bader, Jüri Reimand, Anna Goldenberg, Vijay Ramaswamy, Michael D. Taylor

Research output: Contribution to journalArticle

Abstract

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Original languageEnglish (US)
Pages (from-to)737-754.e6
JournalCancer Cell
Volume31
Issue number6
DOIs
StatePublished - Jun 12 2017

Fingerprint

Medulloblastoma
DNA Methylation
Cluster Analysis
Clinical Trials
Genome
Gene Expression

Keywords

  • copy number
  • gene expression
  • integrative clustering
  • medulloblastoma
  • methylation
  • subgroups

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Cavalli, F. M. G., Remke, M., Rampasek, L., Peacock, J., Shih, D. J. H., Luu, B., ... Taylor, M. D. (2017). Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell, 31(6), 737-754.e6. https://doi.org/10.1016/j.ccell.2017.05.005

Intertumoral Heterogeneity within Medulloblastoma Subgroups. / Cavalli, Florence M.G.; Remke, Marc; Rampasek, Ladislav; Peacock, John; Shih, David J.H.; Luu, Betty; Garzia, Livia; Torchia, Jonathon; Nor, Carolina; Morrissy, A. Sorana; Agnihotri, Sameer; Thompson, Yuan Yao; Kuzan-Fischer, Claudia M.; Farooq, Hamza; Isaev, Keren; Daniels, Craig; Cho, Byung Kyu; Kim, Seung Ki; Wang, Kyu Chang; Lee, Ji Yeoun; Grajkowska, Wieslawa A.; Perek-Polnik, Marta; Vasiljevic, Alexandre; Faure-Conter, Cecile; Jouvet, Anne; Giannini, Caterina; Nageswara Rao, Amulya A.; Li, Kay Ka Wai; Ng, Ho Keung; Eberhart, Charles G; Pollack, Ian F.; Hamilton, Ronald L.; Gillespie, G. Yancey; Olson, James M.; Leary, Sarah; Weiss, William A.; Lach, Boleslaw; Chambless, Lola B.; Thompson, Reid C.; Cooper, Michael K.; Vibhakar, Rajeev; Hauser, Peter; van Veelen, Marie Lise C.; Kros, Johan M.; French, Pim J.; Ra, Young Shin; Kumabe, Toshihiro; López-Aguilar, Enrique; Zitterbart, Karel; Sterba, Jaroslav; Finocchiaro, Gaetano; Massimino, Maura; Van Meir, Erwin G.; Osuka, Satoru; Shofuda, Tomoko; Klekner, Almos; Zollo, Massimo; Leonard, Jeffrey R.; Rubin, Joshua B.; Jabado, Nada; Albrecht, Steffen; Mora, Jaume; Van Meter, Timothy E.; Jung, Shin; Moore, Andrew S.; Hallahan, Andrew R.; Chan, Jennifer A.; Tirapelli, Daniela P.C.; Carlotti, Carlos G.; Fouladi, Maryam; Pimentel, José; Faria, Claudia C.; Saad, Ali G.; Massimi, Luca; Liau, Linda M.; Wheeler, Helen; Nakamura, Hideo; Elbabaa, Samer K.; Perezpeña-Diazconti, Mario; Chico Ponce de León, Fernando; Robinson, Shenandoah; Zapotocky, Michal; Lassaletta, Alvaro; Huang, Annie; Hawkins, Cynthia E.; Tabori, Uri; Bouffet, Eric; Bartels, Ute; Dirks, Peter B.; Rutka, James T.; Bader, Gary D.; Reimand, Jüri; Goldenberg, Anna; Ramaswamy, Vijay; Taylor, Michael D.

In: Cancer Cell, Vol. 31, No. 6, 12.06.2017, p. 737-754.e6.

Research output: Contribution to journalArticle

Cavalli, FMG, Remke, M, Rampasek, L, Peacock, J, Shih, DJH, Luu, B, Garzia, L, Torchia, J, Nor, C, Morrissy, AS, Agnihotri, S, Thompson, YY, Kuzan-Fischer, CM, Farooq, H, Isaev, K, Daniels, C, Cho, BK, Kim, SK, Wang, KC, Lee, JY, Grajkowska, WA, Perek-Polnik, M, Vasiljevic, A, Faure-Conter, C, Jouvet, A, Giannini, C, Nageswara Rao, AA, Li, KKW, Ng, HK, Eberhart, CG, Pollack, IF, Hamilton, RL, Gillespie, GY, Olson, JM, Leary, S, Weiss, WA, Lach, B, Chambless, LB, Thompson, RC, Cooper, MK, Vibhakar, R, Hauser, P, van Veelen, MLC, Kros, JM, French, PJ, Ra, YS, Kumabe, T, López-Aguilar, E, Zitterbart, K, Sterba, J, Finocchiaro, G, Massimino, M, Van Meir, EG, Osuka, S, Shofuda, T, Klekner, A, Zollo, M, Leonard, JR, Rubin, JB, Jabado, N, Albrecht, S, Mora, J, Van Meter, TE, Jung, S, Moore, AS, Hallahan, AR, Chan, JA, Tirapelli, DPC, Carlotti, CG, Fouladi, M, Pimentel, J, Faria, CC, Saad, AG, Massimi, L, Liau, LM, Wheeler, H, Nakamura, H, Elbabaa, SK, Perezpeña-Diazconti, M, Chico Ponce de León, F, Robinson, S, Zapotocky, M, Lassaletta, A, Huang, A, Hawkins, CE, Tabori, U, Bouffet, E, Bartels, U, Dirks, PB, Rutka, JT, Bader, GD, Reimand, J, Goldenberg, A, Ramaswamy, V & Taylor, MD 2017, 'Intertumoral Heterogeneity within Medulloblastoma Subgroups', Cancer Cell, vol. 31, no. 6, pp. 737-754.e6. https://doi.org/10.1016/j.ccell.2017.05.005
Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B et al. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell. 2017 Jun 12;31(6):737-754.e6. https://doi.org/10.1016/j.ccell.2017.05.005
Cavalli, Florence M.G. ; Remke, Marc ; Rampasek, Ladislav ; Peacock, John ; Shih, David J.H. ; Luu, Betty ; Garzia, Livia ; Torchia, Jonathon ; Nor, Carolina ; Morrissy, A. Sorana ; Agnihotri, Sameer ; Thompson, Yuan Yao ; Kuzan-Fischer, Claudia M. ; Farooq, Hamza ; Isaev, Keren ; Daniels, Craig ; Cho, Byung Kyu ; Kim, Seung Ki ; Wang, Kyu Chang ; Lee, Ji Yeoun ; Grajkowska, Wieslawa A. ; Perek-Polnik, Marta ; Vasiljevic, Alexandre ; Faure-Conter, Cecile ; Jouvet, Anne ; Giannini, Caterina ; Nageswara Rao, Amulya A. ; Li, Kay Ka Wai ; Ng, Ho Keung ; Eberhart, Charles G ; Pollack, Ian F. ; Hamilton, Ronald L. ; Gillespie, G. Yancey ; Olson, James M. ; Leary, Sarah ; Weiss, William A. ; Lach, Boleslaw ; Chambless, Lola B. ; Thompson, Reid C. ; Cooper, Michael K. ; Vibhakar, Rajeev ; Hauser, Peter ; van Veelen, Marie Lise C. ; Kros, Johan M. ; French, Pim J. ; Ra, Young Shin ; Kumabe, Toshihiro ; López-Aguilar, Enrique ; Zitterbart, Karel ; Sterba, Jaroslav ; Finocchiaro, Gaetano ; Massimino, Maura ; Van Meir, Erwin G. ; Osuka, Satoru ; Shofuda, Tomoko ; Klekner, Almos ; Zollo, Massimo ; Leonard, Jeffrey R. ; Rubin, Joshua B. ; Jabado, Nada ; Albrecht, Steffen ; Mora, Jaume ; Van Meter, Timothy E. ; Jung, Shin ; Moore, Andrew S. ; Hallahan, Andrew R. ; Chan, Jennifer A. ; Tirapelli, Daniela P.C. ; Carlotti, Carlos G. ; Fouladi, Maryam ; Pimentel, José ; Faria, Claudia C. ; Saad, Ali G. ; Massimi, Luca ; Liau, Linda M. ; Wheeler, Helen ; Nakamura, Hideo ; Elbabaa, Samer K. ; Perezpeña-Diazconti, Mario ; Chico Ponce de León, Fernando ; Robinson, Shenandoah ; Zapotocky, Michal ; Lassaletta, Alvaro ; Huang, Annie ; Hawkins, Cynthia E. ; Tabori, Uri ; Bouffet, Eric ; Bartels, Ute ; Dirks, Peter B. ; Rutka, James T. ; Bader, Gary D. ; Reimand, Jüri ; Goldenberg, Anna ; Ramaswamy, Vijay ; Taylor, Michael D. / Intertumoral Heterogeneity within Medulloblastoma Subgroups. In: Cancer Cell. 2017 ; Vol. 31, No. 6. pp. 737-754.e6.
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AU - Cavalli, Florence M.G.

AU - Remke, Marc

AU - Rampasek, Ladislav

AU - Peacock, John

AU - Shih, David J.H.

AU - Luu, Betty

AU - Garzia, Livia

AU - Torchia, Jonathon

AU - Nor, Carolina

AU - Morrissy, A. Sorana

AU - Agnihotri, Sameer

AU - Thompson, Yuan Yao

AU - Kuzan-Fischer, Claudia M.

AU - Farooq, Hamza

AU - Isaev, Keren

AU - Daniels, Craig

AU - Cho, Byung Kyu

AU - Kim, Seung Ki

AU - Wang, Kyu Chang

AU - Lee, Ji Yeoun

AU - Grajkowska, Wieslawa A.

AU - Perek-Polnik, Marta

AU - Vasiljevic, Alexandre

AU - Faure-Conter, Cecile

AU - Jouvet, Anne

AU - Giannini, Caterina

AU - Nageswara Rao, Amulya A.

AU - Li, Kay Ka Wai

AU - Ng, Ho Keung

AU - Eberhart, Charles G

AU - Pollack, Ian F.

AU - Hamilton, Ronald L.

AU - Gillespie, G. Yancey

AU - Olson, James M.

AU - Leary, Sarah

AU - Weiss, William A.

AU - Lach, Boleslaw

AU - Chambless, Lola B.

AU - Thompson, Reid C.

AU - Cooper, Michael K.

AU - Vibhakar, Rajeev

AU - Hauser, Peter

AU - van Veelen, Marie Lise C.

AU - Kros, Johan M.

AU - French, Pim J.

AU - Ra, Young Shin

AU - Kumabe, Toshihiro

AU - López-Aguilar, Enrique

AU - Zitterbart, Karel

AU - Sterba, Jaroslav

AU - Finocchiaro, Gaetano

AU - Massimino, Maura

AU - Van Meir, Erwin G.

AU - Osuka, Satoru

AU - Shofuda, Tomoko

AU - Klekner, Almos

AU - Zollo, Massimo

AU - Leonard, Jeffrey R.

AU - Rubin, Joshua B.

AU - Jabado, Nada

AU - Albrecht, Steffen

AU - Mora, Jaume

AU - Van Meter, Timothy E.

AU - Jung, Shin

AU - Moore, Andrew S.

AU - Hallahan, Andrew R.

AU - Chan, Jennifer A.

AU - Tirapelli, Daniela P.C.

AU - Carlotti, Carlos G.

AU - Fouladi, Maryam

AU - Pimentel, José

AU - Faria, Claudia C.

AU - Saad, Ali G.

AU - Massimi, Luca

AU - Liau, Linda M.

AU - Wheeler, Helen

AU - Nakamura, Hideo

AU - Elbabaa, Samer K.

AU - Perezpeña-Diazconti, Mario

AU - Chico Ponce de León, Fernando

AU - Robinson, Shenandoah

AU - Zapotocky, Michal

AU - Lassaletta, Alvaro

AU - Huang, Annie

AU - Hawkins, Cynthia E.

AU - Tabori, Uri

AU - Bouffet, Eric

AU - Bartels, Ute

AU - Dirks, Peter B.

AU - Rutka, James T.

AU - Bader, Gary D.

AU - Reimand, Jüri

AU - Goldenberg, Anna

AU - Ramaswamy, Vijay

AU - Taylor, Michael D.

PY - 2017/6/12

Y1 - 2017/6/12

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AB - While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

KW - copy number

KW - gene expression

KW - integrative clustering

KW - medulloblastoma

KW - methylation

KW - subgroups

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