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1. Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Author: Hendrikse, Liam D, Hendrikse, Liam D, Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H, Erickson, Anders W, Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L, Shokouhian, Mohammad, Suárez, Raúl A, Ly, Michelle, Borlase, Stephanie, Scott, David S, Vladoiu, Maria C, Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y, Kumar, Sachin A, Balin, Polina, Visvanathan, Abhirami, Lee, John JY, Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L, Luu, Betty, Bérubé, Pierre, Wang, Yu C, Pfister, Stefan M, Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A, Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J, Kros, Johan M, Zitterbart, Karel, Bailey, Swneke D, Eberhart, Charles G, Rao, Amulya AN, Giannini, Caterina, Olson, James M, Garami, Miklós, Hauser, Peter, Phillips, Joanna J, Ra, Young S, de Torres, Carmen, Mora, Jaume, Li, Kay KW, Ng, Ho-Keung, Poon, Wai S, Pollack, Ian F, López-Aguilar, Enrique, Gillespie, G Yancey, Van Meter, Timothy E, Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S, Van Meir, Erwin G, Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G, Faria, Claudia C, Roussel, Martine F, Boop, Frederick, Chan, Jennifer A, Aldinger, Kimberly A, Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E, Thompson, Eric M, Hendrikse, Liam D, Hendrikse, Liam D, Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H, Erickson, Anders W, Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L, Shokouhian, Mohammad, Suárez, Raúl A, Ly, Michelle, Borlase, Stephanie, Scott, David S, Vladoiu, Maria C, Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y, Kumar, Sachin A, Balin, Polina, Visvanathan, Abhirami, Lee, John JY, Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L, Luu, Betty, Bérubé, Pierre, Wang, Yu C, Pfister, Stefan M, Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A, Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J, Kros, Johan M, Zitterbart, Karel, Bailey, Swneke D, Eberhart, Charles G, Rao, Amulya AN, Giannini, Caterina, Olson, James M, Garami, Miklós, Hauser, Peter, Phillips, Joanna J, Ra, Young S, de Torres, Carmen, Mora, Jaume, Li, Kay KW, Ng, Ho-Keung, Poon, Wai S, Pollack, Ian F, López-Aguilar, Enrique, Gillespie, G Yancey, Van Meter, Timothy E, Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S, Van Meir, Erwin G, Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G, Faria, Claudia C, Roussel, Martine F, Boop, Frederick, Chan, Jennifer A, Aldinger, Kimberly A, Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E, and Thompson, Eric M
Abstract: Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
Published: 2022

2. Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

Author: Bluemel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascao, Rita, Custodia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike, Stuehler, Kai, Meyer, Frauke-Dorothee, Goebbels, Sarah, Malzkorn, Bastian, Liebau, Max C., Barata, Joao T., Jeibmann, Astrid, Kerl, Kornelius, Erkek, Serap, Kool, Marcel, Pfister, Stefan M., Johann, Pascal D., Fruehwald, Michael C., Borkhardt, Arndt, Reifenberger, Guido, Faria, Claudia C., Fischer, Ute, Hasselblatt, Martin, Bartl, Jasmin, Remke, Marc, Bluemel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascao, Rita, Custodia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike, Stuehler, Kai, Meyer, Frauke-Dorothee, Goebbels, Sarah, Malzkorn, Bastian, Liebau, Max C., Barata, Joao T., Jeibmann, Astrid, Kerl, Kornelius, Erkek, Serap, Kool, Marcel, Pfister, Stefan M., Johann, Pascal D., Fruehwald, Michael C., Borkhardt, Arndt, Reifenberger, Guido, Faria, Claudia C., Fischer, Ute, Hasselblatt, Martin, Bartl, Jasmin, and Remke, Marc
Abstract: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.
Published: 2022

3. The transcriptional landscape of Shh medulloblastoma.

Author: Skowron, Patryk, Skowron, Patryk, Farooq, Hamza, Cavalli, Florence MG, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John JY, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, Taylor, Michael D, Skowron, Patryk, Skowron, Patryk, Farooq, Hamza, Cavalli, Florence MG, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John JY, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D
Abstract: Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
Published: 2021

4. The transcriptional landscape of Shh medulloblastoma.

Author: Skowron, Patryk, Skowron, Patryk, Farooq, Hamza, Cavalli, Florence MG, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John JY, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, Taylor, Michael D, Skowron, Patryk, Skowron, Patryk, Farooq, Hamza, Cavalli, Florence MG, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John JY, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D
Abstract: Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
Published: 2021

5. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Author: Nobre, Liana, Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Nageswara Rao, Amulya A, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, Ramaswamy, Vijay, Nobre, Liana, Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Nageswara Rao, Amulya A, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, and Ramaswamy, Vijay
Abstract: Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
Published: 2020

6. Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

Author: de Medeiros, Cynthia B, de Medeiros, Cynthia B, Moxon-Emre, Iska, Scantlebury, Nadia, Malkin, David, Ramaswamy, Vijay, Decker, Alexandra, Law, Nicole, Kumabe, Toshihiro, Leonard, Jeffrey, Rubin, Josh, Jung, Shin, Kim, Seung-Ki, Gupta, Nalin, Weiss, William, Faria, Claudia C, Vibhakar, Rajeev, Lafay-Cousin, Lucie, Chan, Jennifer, Kros, Johan M, Janzen, Laura, Taylor, Michael D, Bouffet, Eric, Mabbott, Donald J, de Medeiros, Cynthia B, de Medeiros, Cynthia B, Moxon-Emre, Iska, Scantlebury, Nadia, Malkin, David, Ramaswamy, Vijay, Decker, Alexandra, Law, Nicole, Kumabe, Toshihiro, Leonard, Jeffrey, Rubin, Josh, Jung, Shin, Kim, Seung-Ki, Gupta, Nalin, Weiss, William, Faria, Claudia C, Vibhakar, Rajeev, Lafay-Cousin, Lucie, Chan, Jennifer, Kros, Johan M, Janzen, Laura, Taylor, Michael D, Bouffet, Eric, and Mabbott, Donald J
Abstract: BackgroundUnderstanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.MethodsSeventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.ResultsThe majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P < .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup.ConclusionsBy examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes.
Published: 2020

7. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Author: Nobre, Liana, Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Nageswara Rao, Amulya A, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, Ramaswamy, Vijay, Nobre, Liana, Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Nageswara Rao, Amulya A, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, and Ramaswamy, Vijay
Abstract: Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
Published: 2020

8. Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

Author: de Medeiros, Cynthia B, de Medeiros, Cynthia B, Moxon-Emre, Iska, Scantlebury, Nadia, Malkin, David, Ramaswamy, Vijay, Decker, Alexandra, Law, Nicole, Kumabe, Toshihiro, Leonard, Jeffrey, Rubin, Josh, Jung, Shin, Kim, Seung-Ki, Gupta, Nalin, Weiss, William, Faria, Claudia C, Vibhakar, Rajeev, Lafay-Cousin, Lucie, Chan, Jennifer, Kros, Johan M, Janzen, Laura, Taylor, Michael D, Bouffet, Eric, Mabbott, Donald J, de Medeiros, Cynthia B, de Medeiros, Cynthia B, Moxon-Emre, Iska, Scantlebury, Nadia, Malkin, David, Ramaswamy, Vijay, Decker, Alexandra, Law, Nicole, Kumabe, Toshihiro, Leonard, Jeffrey, Rubin, Josh, Jung, Shin, Kim, Seung-Ki, Gupta, Nalin, Weiss, William, Faria, Claudia C, Vibhakar, Rajeev, Lafay-Cousin, Lucie, Chan, Jennifer, Kros, Johan M, Janzen, Laura, Taylor, Michael D, Bouffet, Eric, and Mabbott, Donald J
Abstract: BackgroundUnderstanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.MethodsSeventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.ResultsThe majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P < .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup.ConclusionsBy examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes.
Published: 2020

9. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Author: Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A., Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie Lise, French, Pim J., Van Meir, Erwin G., Weiss, William A., Gupta, Nalin, Pollack, Ian F., Hamilton, Ronald L., Nageswara Rao, Amulya A., Giannini, Caterina, Rubin, Joshua B., Moore, Andrew S., Chambless, Lola B., Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E., Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C., Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G., Olson, James M., Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E., Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A., Taylor, Michael D., Yip, Stephen, Hansford, Jordan R., Bouffet, Eric, Ramaswamy, Vijay, Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A., Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie Lise, French, Pim J., Van Meir, Erwin G., Weiss, William A., Gupta, Nalin, Pollack, Ian F., Hamilton, Ronald L., Nageswara Rao, Amulya A., Giannini, Caterina, Rubin, Joshua B., Moore, Andrew S., Chambless, Lola B., Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E., Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C., Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G., Olson, James M., Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E., Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A., Taylor, Michael D., Yip, Stephen, Hansford, Jordan R., Bouffet, Eric, and Ramaswamy, Vijay
Abstract: Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763–0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
Published: 2020

10. Heterogeneity within the PF-EPN-B ependymoma subgroup.

Author: Cavalli, Florence MG, Cavalli, Florence MG, Hübner, Jens-Martin, Sharma, Tanvi, Luu, Betty, Sill, Martin, Zapotocky, Michal, Mack, Stephen C, Witt, Hendrik, Lin, Tong, Shih, David JH, Ho, Ben, Santi, Mariarita, Emery, Lyndsey, Hukin, Juliette, Dunham, Christopher, McLendon, Roger E, Lipp, Eric S, Gururangan, Sridharan, Grossbach, Andrew, French, Pim, Kros, Johan M, van Veelen, Marie-Lise C, Rao, Amulya A Nageswara, Giannini, Caterina, Leary, Sarah, Jung, Shin, Faria, Claudia C, Mora, Jaume, Schüller, Ulrich, Alonso, Marta M, Chan, Jennifer A, Klekner, Almos, Chambless, Lola B, Hwang, Eugene I, Massimino, Maura, Eberhart, Charles G, Karajannis, Matthias A, Lu, Benjamin, Liau, Linda M, Zollo, Massimo, Ferrucci, Veronica, Carlotti, Carlos, Tirapelli, Daniela PC, Tabori, Uri, Bouffet, Eric, Ryzhova, Marina, Ellison, David W, Merchant, Thomas E, Gilbert, Mark R, Armstrong, Terri S, Korshunov, Andrey, Pfister, Stefan M, Taylor, Michael D, Aldape, Kenneth, Pajtler, Kristian W, Kool, Marcel, Ramaswamy, Vijay, Cavalli, Florence MG, Cavalli, Florence MG, Hübner, Jens-Martin, Sharma, Tanvi, Luu, Betty, Sill, Martin, Zapotocky, Michal, Mack, Stephen C, Witt, Hendrik, Lin, Tong, Shih, David JH, Ho, Ben, Santi, Mariarita, Emery, Lyndsey, Hukin, Juliette, Dunham, Christopher, McLendon, Roger E, Lipp, Eric S, Gururangan, Sridharan, Grossbach, Andrew, French, Pim, Kros, Johan M, van Veelen, Marie-Lise C, Rao, Amulya A Nageswara, Giannini, Caterina, Leary, Sarah, Jung, Shin, Faria, Claudia C, Mora, Jaume, Schüller, Ulrich, Alonso, Marta M, Chan, Jennifer A, Klekner, Almos, Chambless, Lola B, Hwang, Eugene I, Massimino, Maura, Eberhart, Charles G, Karajannis, Matthias A, Lu, Benjamin, Liau, Linda M, Zollo, Massimo, Ferrucci, Veronica, Carlotti, Carlos, Tirapelli, Daniela PC, Tabori, Uri, Bouffet, Eric, Ryzhova, Marina, Ellison, David W, Merchant, Thomas E, Gilbert, Mark R, Armstrong, Terri S, Korshunov, Andrey, Pfister, Stefan M, Taylor, Michael D, Aldape, Kenneth, Pajtler, Kristian W, Kool, Marcel, and Ramaswamy, Vijay
Abstract: Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalize
Published: 2018

11. Intertumoral Heterogeneity within Medulloblastoma Subgroups.

Author: Cavalli, Florence MG, Cavalli, Florence MG, Remke, Marc, Rampasek, Ladislav, Peacock, John, Shih, David JH, 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 PC, 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, Cavalli, Florence MG, Cavalli, Florence MG, Remke, Marc, Rampasek, Ladislav, Peacock, John, Shih, David JH, 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 PC, 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, and Taylor, Michael D
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.
Published: 2017

12. Intertumoral Heterogeneity within Medulloblastoma Subgroups

Author: 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, Almo, 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., 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, Almo, 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, and Taylor, Michael D.
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.
Published: 2017

13. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

Author: Thompson, Eric M, Thompson, Eric M, Hielscher, Thomas, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, McLendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David CY, Seow, Wan Tew, Chang, Kenneth TE, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leos, Hortobágyi, Tibor, Klekner, Almos, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David JH, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David TW, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, James, Kulkarni, Abhaya, Thompson, Eric M, Thompson, Eric M, Hielscher, Thomas, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, McLendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David CY, Seow, Wan Tew, Chang, Kenneth TE, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leos, Hortobágyi, Tibor, Klekner, Almos, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David JH, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David TW, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, James, and Kulkarni, Abhaya
Abstract: BackgroundPatients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.MethodsWe retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.FindingsWe included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable
Published: 2016

14. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

Author: Thompson, Eric M, Thompson, Eric M, Hielscher, Thomas, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, McLendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David CY, Seow, Wan Tew, Chang, Kenneth TE, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leos, Hortobágyi, Tibor, Klekner, Almos, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David JH, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David TW, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, James, Kulkarni, Abhaya, Thompson, Eric M, Thompson, Eric M, Hielscher, Thomas, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, McLendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David CY, Seow, Wan Tew, Chang, Kenneth TE, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leos, Hortobágyi, Tibor, Klekner, Almos, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David JH, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David TW, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, James, and Kulkarni, Abhaya
Abstract: BackgroundPatients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.MethodsWe retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.FindingsWe included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable
Published: 2016

15. Divergent clonal selection dominates medulloblastoma at recurrence.

Author: Morrissy, A Sorana, Morrissy, A Sorana, Garzia, Livia, Shih, David JH, Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence MG, Ramaswamy, Vijay, Lindsay, Patricia E, Jelveh, Salomeh, Donovan, Laura K, Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L, Ma, Yusanne, Tse, Kane, Zeng, Thomas, Shumansky, Karey, Roth, Andrew JL, Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L, Lee, John JY, Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C, Manno, Alex, Michealraj, KA, Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y, Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron SN, Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D, Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I, Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q, Schein, Jacqueline E, Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C, Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F, Hamilton, Ronald L, Li, Xiao-Nan, Bendel, Anne E, Fults, Daniel W, Walter, Andrew W, Kumabe, Toshihiro, Tominaga, Teiji, Collins, V Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H, Garvin, James H, Stearns, Duncan S, Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E, Tirapelli, Daniela PC, Carlotti, Carlos G, Wheeler, Helen, Hallahan, Andrew R, Ingram, Wendy, MacDonald, Tobey J, Olson, Jeffrey J, Van Meir, Erwin G, Lee, Ji-Yeoun, Wang, Kyu-Chang, Morrissy, A Sorana, Morrissy, A Sorana, Garzia, Livia, Shih, David JH, Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence MG, Ramaswamy, Vijay, Lindsay, Patricia E, Jelveh, Salomeh, Donovan, Laura K, Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L, Ma, Yusanne, Tse, Kane, Zeng, Thomas, Shumansky, Karey, Roth, Andrew JL, Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L, Lee, John JY, Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C, Manno, Alex, Michealraj, KA, Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y, Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron SN, Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D, Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I, Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q, Schein, Jacqueline E, Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C, Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F, Hamilton, Ronald L, Li, Xiao-Nan, Bendel, Anne E, Fults, Daniel W, Walter, Andrew W, Kumabe, Toshihiro, Tominaga, Teiji, Collins, V Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H, Garvin, James H, Stearns, Duncan S, Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E, Tirapelli, Daniela PC, Carlotti, Carlos G, Wheeler, Helen, Hallahan, Andrew R, Ingram, Wendy, MacDonald, Tobey J, Olson, Jeffrey J, Van Meir, Erwin G, Lee, Ji-Yeoun, and Wang, Kyu-Chang
Abstract: The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Published: 2016

16. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis.

Author: Ramaswamy, Vijay, Ramaswamy, Vijay, Hielscher, Thomas, Mack, Stephen C, Lassaletta, Alvaro, Lin, Tong, Pajtler, Kristian W, Jones, David TW, Luu, Betty, Cavalli, Florence MG, Aldape, Kenneth, Remke, Marc, Mynarek, Martin, Rutkowski, Stefan, Gururangan, Sridharan, McLendon, Roger E, Lipp, Eric S, Dunham, Christopher, Hukin, Juliette, Eisenstat, David D, Fulton, Dorcas, van Landeghem, Frank KH, Santi, Mariarita, van Veelen, Marie-Lise C, Van Meir, Erwin G, Osuka, Satoru, Fan, Xing, Muraszko, Karin M, Tirapelli, Daniela PC, Oba-Shinjo, Sueli M, Marie, Suely KN, Carlotti, Carlos G, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Faria, Claudia C, Nunes, Sofia, Mora, Jaume, Hamilton, Ronald L, Hauser, Peter, Jabado, Nada, Petrecca, Kevin, Jung, Shin, Massimi, Luca, Zollo, Massimo, Cinalli, Giuseppe, Bognár, László, Klekner, Almos, Hortobágyi, Tibor, Leary, Sarah, Ermoian, Ralph P, Olson, James M, Leonard, Jeffrey R, Gardner, Corrine, Grajkowska, Wieslawa A, Chambless, Lola B, Cain, Jason, Eberhart, Charles G, Ahsan, Sama, Massimino, Maura, Giangaspero, Felice, Buttarelli, Francesca R, Packer, Roger J, Emery, Lyndsey, Yong, William H, Soto, Horacio, Liau, Linda M, Everson, Richard, Grossbach, Andrew, Shalaby, Tarek, Grotzer, Michael, Karajannis, Matthias A, Zagzag, David, Wheeler, Helen, von Hoff, Katja, Alonso, Marta M, Tuñon, Teresa, Schüller, Ulrich, Zitterbart, Karel, Sterba, Jaroslav, Chan, Jennifer A, Guzman, Miguel, Elbabaa, Samer K, Colman, Howard, Dhall, Girish, Fisher, Paul G, Fouladi, Maryam, Gajjar, Amar, Goldman, Stewart, Hwang, Eugene, Kool, Marcel, Ladha, Harshad, Vera-Bolanos, Elizabeth, Wani, Khalida, Lieberman, Frank, Mikkelsen, Tom, Omuro, Antonio M, Pollack, Ian F, Prados, Michael, Robins, H Ian, Soffietti, Riccardo, Ramaswamy, Vijay, Ramaswamy, Vijay, Hielscher, Thomas, Mack, Stephen C, Lassaletta, Alvaro, Lin, Tong, Pajtler, Kristian W, Jones, David TW, Luu, Betty, Cavalli, Florence MG, Aldape, Kenneth, Remke, Marc, Mynarek, Martin, Rutkowski, Stefan, Gururangan, Sridharan, McLendon, Roger E, Lipp, Eric S, Dunham, Christopher, Hukin, Juliette, Eisenstat, David D, Fulton, Dorcas, van Landeghem, Frank KH, Santi, Mariarita, van Veelen, Marie-Lise C, Van Meir, Erwin G, Osuka, Satoru, Fan, Xing, Muraszko, Karin M, Tirapelli, Daniela PC, Oba-Shinjo, Sueli M, Marie, Suely KN, Carlotti, Carlos G, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Faria, Claudia C, Nunes, Sofia, Mora, Jaume, Hamilton, Ronald L, Hauser, Peter, Jabado, Nada, Petrecca, Kevin, Jung, Shin, Massimi, Luca, Zollo, Massimo, Cinalli, Giuseppe, Bognár, László, Klekner, Almos, Hortobágyi, Tibor, Leary, Sarah, Ermoian, Ralph P, Olson, James M, Leonard, Jeffrey R, Gardner, Corrine, Grajkowska, Wieslawa A, Chambless, Lola B, Cain, Jason, Eberhart, Charles G, Ahsan, Sama, Massimino, Maura, Giangaspero, Felice, Buttarelli, Francesca R, Packer, Roger J, Emery, Lyndsey, Yong, William H, Soto, Horacio, Liau, Linda M, Everson, Richard, Grossbach, Andrew, Shalaby, Tarek, Grotzer, Michael, Karajannis, Matthias A, Zagzag, David, Wheeler, Helen, von Hoff, Katja, Alonso, Marta M, Tuñon, Teresa, Schüller, Ulrich, Zitterbart, Karel, Sterba, Jaroslav, Chan, Jennifer A, Guzman, Miguel, Elbabaa, Samer K, Colman, Howard, Dhall, Girish, Fisher, Paul G, Fouladi, Maryam, Gajjar, Amar, Goldman, Stewart, Hwang, Eugene, Kool, Marcel, Ladha, Harshad, Vera-Bolanos, Elizabeth, Wani, Khalida, Lieberman, Frank, Mikkelsen, Tom, Omuro, Antonio M, Pollack, Ian F, Prados, Michael, Robins, H Ian, and Soffietti, Riccardo
Abstract: PurposePosterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.MethodsFour independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.ResultsMolecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.ConclusionThe most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
Published: 2016

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

Author: Torchia, Jonathon, Torchia, Jonathon, Golbourn, Brian, Feng, Shengrui, Ho, King Ching, Sin-Chan, Patrick, Vasiljevic, Alexandre, Norman, Joseph D, Guilhamon, Paul, Garzia, Livia, Agamez, Natalia R, Lu, Mei, Chan, Tiffany S, Picard, Daniel, de Antonellis, Pasqualino, Khuong-Quang, Dong-Anh, Planello, Aline C, Zeller, Constanze, Barsyte-Lovejoy, Dalia, Lafay-Cousin, Lucie, Letourneau, Louis, Bourgey, Mathieu, Yu, Man, Gendoo, Deena MA, Dzamba, Misko, Barszczyk, Mark, Medina, Tiago, Riemenschneider, Alexandra N, Morrissy, A Sorana, Ra, Young-Shin, Ramaswamy, Vijay, Remke, Marc, Dunham, Christopher P, Yip, Stephen, Ng, Ho-Keung, Lu, Jian-Qiang, Mehta, Vivek, Albrecht, Steffen, Pimentel, Jose, Chan, Jennifer A, Somers, Gino R, Faria, Claudia C, Roque, Lucia, Fouladi, Maryam, Hoffman, Lindsey M, Moore, Andrew S, Wang, Yin, Choi, Seung Ah, Hansford, Jordan R, Catchpoole, Daniel, Birks, Diane K, Foreman, Nicholas K, Strother, Doug, Klekner, Almos, Bognár, Laszló, Garami, Miklós, Hauser, Péter, Hortobágyi, Tibor, Wilson, Beverly, Hukin, Juliette, Carret, Anne-Sophie, Van Meter, Timothy E, Hwang, Eugene I, Gajjar, Amar, Chiou, Shih-Hwa, Nakamura, Hideo, Toledano, Helen, Fried, Iris, Fults, Daniel, Wataya, Takafumi, Fryer, Chris, Eisenstat, David D, Scheinemann, Katrin, Fleming, Adam J, Johnston, Donna L, Michaud, Jean, Zelcer, Shayna, Hammond, Robert, Afzal, Samina, Ramsay, David A, Sirachainan, Nongnuch, Hongeng, Suradej, Larbcharoensub, Noppadol, Grundy, Richard G, Lulla, Rishi R, Fangusaro, Jason R, Druker, Harriet, Bartels, Ute, Grant, Ronald, Malkin, David, McGlade, C Jane, Nicolaides, Theodore, Tihan, Tarik, Phillips, Joanna, Majewski, Jacek, Montpetit, Alexandre, Bourque, Guillaume, Bader, Gary D, Reddy, Alyssa T, Gillespie, G Yancey, Warmuth-Metz, Monika, Torchia, Jonathon, Torchia, Jonathon, Golbourn, Brian, Feng, Shengrui, Ho, King Ching, Sin-Chan, Patrick, Vasiljevic, Alexandre, Norman, Joseph D, Guilhamon, Paul, Garzia, Livia, Agamez, Natalia R, Lu, Mei, Chan, Tiffany S, Picard, Daniel, de Antonellis, Pasqualino, Khuong-Quang, Dong-Anh, Planello, Aline C, Zeller, Constanze, Barsyte-Lovejoy, Dalia, Lafay-Cousin, Lucie, Letourneau, Louis, Bourgey, Mathieu, Yu, Man, Gendoo, Deena MA, Dzamba, Misko, Barszczyk, Mark, Medina, Tiago, Riemenschneider, Alexandra N, Morrissy, A Sorana, Ra, Young-Shin, Ramaswamy, Vijay, Remke, Marc, Dunham, Christopher P, Yip, Stephen, Ng, Ho-Keung, Lu, Jian-Qiang, Mehta, Vivek, Albrecht, Steffen, Pimentel, Jose, Chan, Jennifer A, Somers, Gino R, Faria, Claudia C, Roque, Lucia, Fouladi, Maryam, Hoffman, Lindsey M, Moore, Andrew S, Wang, Yin, Choi, Seung Ah, Hansford, Jordan R, Catchpoole, Daniel, Birks, Diane K, Foreman, Nicholas K, Strother, Doug, Klekner, Almos, Bognár, Laszló, Garami, Miklós, Hauser, Péter, Hortobágyi, Tibor, Wilson, Beverly, Hukin, Juliette, Carret, Anne-Sophie, Van Meter, Timothy E, Hwang, Eugene I, Gajjar, Amar, Chiou, Shih-Hwa, Nakamura, Hideo, Toledano, Helen, Fried, Iris, Fults, Daniel, Wataya, Takafumi, Fryer, Chris, Eisenstat, David D, Scheinemann, Katrin, Fleming, Adam J, Johnston, Donna L, Michaud, Jean, Zelcer, Shayna, Hammond, Robert, Afzal, Samina, Ramsay, David A, Sirachainan, Nongnuch, Hongeng, Suradej, Larbcharoensub, Noppadol, Grundy, Richard G, Lulla, Rishi R, Fangusaro, Jason R, Druker, Harriet, Bartels, Ute, Grant, Ronald, Malkin, David, McGlade, C Jane, Nicolaides, Theodore, Tihan, Tarik, Phillips, Joanna, Majewski, Jacek, Montpetit, Alexandre, Bourque, Guillaume, Bader, Gary D, Reddy, Alyssa T, Gillespie, G Yancey, and Warmuth-Metz, Monika
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.
Published: 2016

18. Divergent clonal selection dominates medulloblastoma at recurrence

Author: Morrissy, A. Sorana, Garzia, Livia, Shih, David J. H., Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence M. G., Ramaswamy, Vijay, Lindsay, Patricia E., Jelveh, Salomeh, Donovan, Laura K., Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L., Ma, Yusanne, Tse, Kane, Zeng, Thoma, Shumansky, Karey, Roth, Andrew J. L., Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L., Lee, John J. Y., Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C., Manno, Alex, Michealraj, K. A., Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y., Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron S. N., Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D., Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I., Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q., Schein, Jacqueline E., Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C., Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F., Hamilton, Ronald L., Li, Xiao-Nan, Bendel, Anne E., Fults, Daniel W., Walter, Andrew W., Kumabe, Toshihiro, Tominaga, Teiji, Collins, V. Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H., Garvin, James H., Stearns, Duncan S., Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E., Tirapelli, Daniela P. C., Carlotti, Carlos G., Wheeler, Helen, Hallahan, Andrew R., Ingram, Wendy, Macdonald, Tobey J., Olson, Jeffrey J., Van Meir, Erwin G., Lee, Ji-Yeoun, Wang, Kyu-Chang, Kim, Seung-Ki, Cho, Byung-Kyu, Pietsch, Torsten, Fleischhack, Gudrun, Tippelt, Stephan, Ra, Young Shin, Bailey, Simon, Lindsey, Janet C., Clifford, Steven C., Eberhart, Charles G., Cooper, Michael K., Packer, Roger J., Massimino, Maura, Garre, Maria Luisa, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia E., Dirks, Peter, Bouffet, Eric, Rutka, James T., Wechsler-Reya, Robert J., Weiss, William A., Collier, Lara S., Dupuy, Adam J., Korshunov, Andrey, Jones, David T. W., Kool, Marcel, Northcott, Paul A., Pfister, Stefan M., Largaespada, David A., Mungall, Andrew J., Moore, Richard A., Jabado, Nada, Bader, Gary D., Jones, Steven J. M., Malkin, David, Marra, Marco A., Taylor, Michael D., Morrissy, A. Sorana, Garzia, Livia, Shih, David J. H., Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence M. G., Ramaswamy, Vijay, Lindsay, Patricia E., Jelveh, Salomeh, Donovan, Laura K., Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L., Ma, Yusanne, Tse, Kane, Zeng, Thoma, Shumansky, Karey, Roth, Andrew J. L., Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L., Lee, John J. Y., Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C., Manno, Alex, Michealraj, K. A., Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y., Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron S. N., Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D., Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I., Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q., Schein, Jacqueline E., Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C., Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F., Hamilton, Ronald L., Li, Xiao-Nan, Bendel, Anne E., Fults, Daniel W., Walter, Andrew W., Kumabe, Toshihiro, Tominaga, Teiji, Collins, V. Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H., Garvin, James H., Stearns, Duncan S., Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E., Tirapelli, Daniela P. C., Carlotti, Carlos G., Wheeler, Helen, Hallahan, Andrew R., Ingram, Wendy, Macdonald, Tobey J., Olson, Jeffrey J., Van Meir, Erwin G., Lee, Ji-Yeoun, Wang, Kyu-Chang, Kim, Seung-Ki, Cho, Byung-Kyu, Pietsch, Torsten, Fleischhack, Gudrun, Tippelt, Stephan, Ra, Young Shin, Bailey, Simon, Lindsey, Janet C., Clifford, Steven C., Eberhart, Charles G., Cooper, Michael K., Packer, Roger J., Massimino, Maura, Garre, Maria Luisa, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia E., Dirks, Peter, Bouffet, Eric, Rutka, James T., Wechsler-Reya, Robert J., Weiss, William A., Collier, Lara S., Dupuy, Adam J., Korshunov, Andrey, Jones, David T. W., Kool, Marcel, Northcott, Paul A., Pfister, Stefan M., Largaespada, David A., Mungall, Andrew J., Moore, Richard A., Jabado, Nada, Bader, Gary D., Jones, Steven J. M., Malkin, David, Marra, Marco A., and Taylor, Michael D.
Abstract: The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Published: 2016

19. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Author: Thompson, Eric M, Hielscher, Thoma, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, Mclendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David C Y, Seow, Wan Tew, Chang, Kenneth T E, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leo, Hortobágyi, Tibor, Klekner, Almo, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David J H, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David T W, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, Jame, Kulkarni, Abhaya, Dirks, Peter, Rutka, James T, Korshunov, Andrey, Pfister, Stefan M, Packer, Roger J, Ramaswamy, Vijay, Taylor, Michael D, Thompson, Eric M, Hielscher, Thoma, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, Mclendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David C Y, Seow, Wan Tew, Chang, Kenneth T E, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leo, Hortobágyi, Tibor, Klekner, Almo, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David J H, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David T W, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, Jame, Kulkarni, Abhaya, Dirks, Peter, Rutka, James T, Korshunov, Andrey, Pfister, Stefan M, Packer, Roger J, Ramaswamy, Vijay, and Taylor, Michael D
Abstract: Background Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. Methods We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm2tumour remaining), or sub-total resection (≥1·5 cm2tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. Findings We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models o
Published: 2016

20. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: A retrospective multicohort analysis

Author: Ramaswamy, Vijay, Hielscher, Thoma, Mack, Stephen C., Lassaletta, Alvaro, Lin, Tong, Pajtler, Kristian W., Jones, David T. W., Luu, Betty, Cavalli, Florence M. G., Aldape, Kenneth, Remke, Marc, Mynarek, Martin, Rutkowski, Stefan, Gururangan, Sridharan, Mclendon, Roger E., Lipp, Eric S., Dunham, Christopher, Hukin, Juliette, Eisenstat, David D., Fulton, Dorca, Van Landeghem, Frank K. H., Santi, Mariarita, Van Veelen, Marie-Lise C., Van Meir, Erwin G., Osuka, Satoru, Fan, Xing, Muraszko, Karin M., Tirapelli, Daniela P. C., Oba-Shinjo, Sueli M., Marie, Suely K. N., Carlotti, Carlos G., Lee, Ji Yeoun, Rao, Amulya A. Nageswara, Giannini, Caterina, Faria, Claudia C., Nunes, Sofia, Mora, Jaume, Hamilton, Ronald L., Hauser, Peter, Jabado, Nada, Petrecca, Kevin, Jung, Shin, Massimi, Luca, Zollo, Massimo, Cinalli, Giuseppe, Bognár, László, Klekner, Almo, Hortobágyi, Tibor, Leary, Sarah, Ermoian, Ralph P., Olson, James M., Leonard, Jeffrey R., Gardner, Corrine, Grajkowska, Wieslawa A., Chambless, Lola B., Cain, Jason, Eberhart, Charles G., Ahsan, Sama, Massimino, Maura, Giangaspero, Felice, Buttarelli, Francesca R., Packer, Roger J., Emery, Lyndsey, Yong, William H., Soto, Horacio, Liau, Linda M., Everson, Richard, Grossbach, Andrew, Shalaby, Tarek, Grotzer, Michael, Karajannis, Matthias A., Zagzag, David, Wheeler, Helen, Von Hoff, Katja, Alonso, Marta M., Tuñon, Teresa, Schüller, Ulrich, Zitterbart, Karel, Sterba, Jaroslav, Chan, Jennifer A., Guzman, Miguel, Elbabaa, Samer K., Colman, Howard, Dhall, Girish, Fisher, Paul G., Fouladi, Maryam, Gajjar, Amar, Goldman, Stewart, Hwang, Eugene, Kool, Marcel, Ladha, Harshad, Vera-Bolanos, Elizabeth, Wani, Khalida, Lieberman, Frank, Mikkelsen, Tom, Omuro, Antonio M., Pollack, Ian F., Prados, Michael, Robins, H. Ian, Soffietti, Riccardo, Wu, Jing, Metellus, Phillipe, Tabori, Uri, Bartels, Ute, Bouffet, Eric, Hawkins, Cynthia E., Rutka, James T., Dirks, Peter, Pfister, Stefan M., Merchant, Thomas E., Gilbert, Mark R., Armstrong, Terri S., Korshunov, Andrey, Ellison, David W., Taylor, Michael D., Ramaswamy, Vijay, Hielscher, Thoma, Mack, Stephen C., Lassaletta, Alvaro, Lin, Tong, Pajtler, Kristian W., Jones, David T. W., Luu, Betty, Cavalli, Florence M. G., Aldape, Kenneth, Remke, Marc, Mynarek, Martin, Rutkowski, Stefan, Gururangan, Sridharan, Mclendon, Roger E., Lipp, Eric S., Dunham, Christopher, Hukin, Juliette, Eisenstat, David D., Fulton, Dorca, Van Landeghem, Frank K. H., Santi, Mariarita, Van Veelen, Marie-Lise C., Van Meir, Erwin G., Osuka, Satoru, Fan, Xing, Muraszko, Karin M., Tirapelli, Daniela P. C., Oba-Shinjo, Sueli M., Marie, Suely K. N., Carlotti, Carlos G., Lee, Ji Yeoun, Rao, Amulya A. Nageswara, Giannini, Caterina, Faria, Claudia C., Nunes, Sofia, Mora, Jaume, Hamilton, Ronald L., Hauser, Peter, Jabado, Nada, Petrecca, Kevin, Jung, Shin, Massimi, Luca, Zollo, Massimo, Cinalli, Giuseppe, Bognár, László, Klekner, Almo, Hortobágyi, Tibor, Leary, Sarah, Ermoian, Ralph P., Olson, James M., Leonard, Jeffrey R., Gardner, Corrine, Grajkowska, Wieslawa A., Chambless, Lola B., Cain, Jason, Eberhart, Charles G., Ahsan, Sama, Massimino, Maura, Giangaspero, Felice, Buttarelli, Francesca R., Packer, Roger J., Emery, Lyndsey, Yong, William H., Soto, Horacio, Liau, Linda M., Everson, Richard, Grossbach, Andrew, Shalaby, Tarek, Grotzer, Michael, Karajannis, Matthias A., Zagzag, David, Wheeler, Helen, Von Hoff, Katja, Alonso, Marta M., Tuñon, Teresa, Schüller, Ulrich, Zitterbart, Karel, Sterba, Jaroslav, Chan, Jennifer A., Guzman, Miguel, Elbabaa, Samer K., Colman, Howard, Dhall, Girish, Fisher, Paul G., Fouladi, Maryam, Gajjar, Amar, Goldman, Stewart, Hwang, Eugene, Kool, Marcel, Ladha, Harshad, Vera-Bolanos, Elizabeth, Wani, Khalida, Lieberman, Frank, Mikkelsen, Tom, Omuro, Antonio M., Pollack, Ian F., Prados, Michael, Robins, H. Ian, Soffietti, Riccardo, Wu, Jing, Metellus, Phillipe, Tabori, Uri, Bartels, Ute, Bouffet, Eric, Hawkins, Cynthia E., Rutka, James T., Dirks, Peter, Pfister, Stefan M., Merchant, Thomas E., Gilbert, Mark R., Armstrong, Terri S., Korshunov, Andrey, Ellison, David W., and Taylor, Michael D.
Abstract: Purpose: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN-PFA and EPN-PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. Methods: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. Results: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN-PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN-PFA, a substantial proportion of patients with EPN-PFB can be cured with surgery alone, and patients with relapsed EPN-PFB can often be treated successfully with delayed external-beam irradiation. Conclusion: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN-PFA and EPN-PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN-PFA, even with adjuvant radiation therapy. Patients with EPN-PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
Published: 2016

21. Molecular subgroups of atypical teratoid rhabdoid tumours in children : an integrated genomic and clinicopathological analysis

Author: 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, Jose, Chan, Jennifer A., Somers, Gino R., Zielenska, Maria, Faria, Claudia C., Roque, Lucia, Baskin, Berivan, Birks, Diane, Foreman, Nick, Strother, Douglas, Klekner, Almos, Garami, Miklos, Hauser, Peter, Hortobagyi, Tibor, Bognar, Laszlo, 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., Schueller, 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, 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, Jose, Chan, Jennifer A., Somers, Gino R., Zielenska, Maria, Faria, Claudia C., Roque, Lucia, Baskin, Berivan, Birks, Diane, Foreman, Nick, Strother, Douglas, Klekner, Almos, Garami, Miklos, Hauser, Peter, Hortobagyi, Tibor, Bognar, Laszlo, 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., Schueller, 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, and Huang, Annie
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 factor
Published: 2015
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22. Cytogenetic prognostication within medulloblastoma subgroups.

Author: Shih, David JH, Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, Taylor, Michael D, Shih, David JH, Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, and Taylor, Michael D
Abstract: PurposeMedulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.Patients and methodsMolecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.ResultsSubgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.ConclusionCombining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
Published: 2014

23. Cytogenetic prognostication within medulloblastoma subgroups.

Author: Shih, David JH, Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, Taylor, Michael D, Shih, David JH, Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, and Taylor, Michael D
Abstract: PurposeMedulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.Patients and methodsMolecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.ResultsSubgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.ConclusionCombining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
Published: 2014

24. Cytogenetic prognostication within medulloblastoma subgroups

Author: Shih, David J. H., Northcott, Paul A., Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M., Garzia, Livia, Peacock, John, Mack, Stephen C., Wu, Xiaochong, Rolider, Adi, Morrissy, A. Sorana, Cavalli, Florence M. G., Jones, David T. W., Zitterbart, Karel, Faria, Claudia C., Schüller, Ulrich, Kren, Leo, Kumabe, Toshihiro, Tominaga, Teiji, Ra, Young Shin, Garami, Mikló, Hauser, Peter, Chan, Jennifer A., Robinson, Shenandoah, Bognár, László, Klekner, Almo, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Bailey, Simon, Lindsey, Janet C., Di Rocco, Concezio, Massimi, Luca, Michiels, Erna M. C., Scherer, Stephen W., Phillips, Joanna J., Gupta, Nalin, Fan, Xing, Muraszko, Karin M., Vibhakar, Rajeev, Eberhart, Charles G., Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J., Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F., Weiss, William A., Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R., Rubin, Joshua B., De Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M., Gajjar, Amar, Packer, Roger J., Rutkowski, Stefan, Pomeroy, Scott L., French, Pim J., Kloosterhof, Nanne K., Kros, Johan M., Van Meir, Erwin G., Clifford, Steven C., Bourdeaut, Franck, Delattre, Olivier, Doz, François F., Hawkins, Cynthia E., Malkin, David, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T., Pfister, Stefan M., Taylor, Michael D., Shih, David J. H., Northcott, Paul A., Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M., Garzia, Livia, Peacock, John, Mack, Stephen C., Wu, Xiaochong, Rolider, Adi, Morrissy, A. Sorana, Cavalli, Florence M. G., Jones, David T. W., Zitterbart, Karel, Faria, Claudia C., Schüller, Ulrich, Kren, Leo, Kumabe, Toshihiro, Tominaga, Teiji, Ra, Young Shin, Garami, Mikló, Hauser, Peter, Chan, Jennifer A., Robinson, Shenandoah, Bognár, László, Klekner, Almo, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Bailey, Simon, Lindsey, Janet C., Di Rocco, Concezio, Massimi, Luca, Michiels, Erna M. C., Scherer, Stephen W., Phillips, Joanna J., Gupta, Nalin, Fan, Xing, Muraszko, Karin M., Vibhakar, Rajeev, Eberhart, Charles G., Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J., Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F., Weiss, William A., Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R., Rubin, Joshua B., De Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M., Gajjar, Amar, Packer, Roger J., Rutkowski, Stefan, Pomeroy, Scott L., French, Pim J., Kloosterhof, Nanne K., Kros, Johan M., Van Meir, Erwin G., Clifford, Steven C., Bourdeaut, Franck, Delattre, Olivier, Doz, François F., Hawkins, Cynthia E., Malkin, David, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T., Pfister, Stefan M., and Taylor, Michael D.
Abstract: Purpose: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials. © 2
Published: 2014

25. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Author: Remke, Marc, Ramaswamy, Vijay, Peacock, John, Shih, David J. H., Koelsche, Christian, Northcott, Paul A., Hill, Nadia, Cavalli, Florence M. G., Kool, Marcel, Wang, Xin, Mack, Stephen C., Barszczyk, Mark, Morrissy, A. Sorana, Wu, Xiaochong, Agnihotri, Sameer, Luu, Betty, Jones, David T. W., Garzia, Livia, Dubuc, Adrian M., Zhukova, Nataliya, Vanner, Robert, Kros, Johan M., French, Pim J., Van Meir, Erwin G., Vibhakar, Rajeev, Zitterbart, Karel, Chan, Jennifer A., Bognár, László, Klekner, Almo, Lach, Boleslaw, Jung, Shin, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Delattre, Oliver O., Bourdeaut, Franck, Doz, François F., Garami, Mikló, Hauser, Peter, Carlotti, Carlos G., Van Meter, Timothy E., Massimi, Luca, Fults, Daniel, Pomeroy, Scott L., Kumabe, Toshiro, Ra, Young Shin, Leonard, Jeffrey R., Elbabaa, Samer K., Mora, Jaume, Rubin, Joshua B., Cho, Yoon-Jae, Mclendon, Roger E., Bigner, Darell D., Eberhart, Charles G., Fouladi, Maryam, Wechsler-Reya, Robert J., Faria, Claudia C., Croul, Sidney E., Huang, Annie, Bouffet, Eric, Hawkins, Cynthia E., Dirks, Peter B., Weiss, William A., Schüller, Ulrich, Pollack, Ian F., Rutkowski, Stefan, Meyronet, David, Jouvet, Anne, Fèvre-Montange, Michelle, Jabado, Nada, Perek-Polnik, Marta, Grajkowska, Wieslawa A., Kim, Seung-Ki, Rutka, James T., Malkin, David, Tabori, Uri, Pfister, Stefan M., Korshunov, Andrey, Von Deimling, Andrea, Taylor, Michael D., Remke, Marc, Ramaswamy, Vijay, Peacock, John, Shih, David J. H., Koelsche, Christian, Northcott, Paul A., Hill, Nadia, Cavalli, Florence M. G., Kool, Marcel, Wang, Xin, Mack, Stephen C., Barszczyk, Mark, Morrissy, A. Sorana, Wu, Xiaochong, Agnihotri, Sameer, Luu, Betty, Jones, David T. W., Garzia, Livia, Dubuc, Adrian M., Zhukova, Nataliya, Vanner, Robert, Kros, Johan M., French, Pim J., Van Meir, Erwin G., Vibhakar, Rajeev, Zitterbart, Karel, Chan, Jennifer A., Bognár, László, Klekner, Almo, Lach, Boleslaw, Jung, Shin, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Delattre, Oliver O., Bourdeaut, Franck, Doz, François F., Garami, Mikló, Hauser, Peter, Carlotti, Carlos G., Van Meter, Timothy E., Massimi, Luca, Fults, Daniel, Pomeroy, Scott L., Kumabe, Toshiro, Ra, Young Shin, Leonard, Jeffrey R., Elbabaa, Samer K., Mora, Jaume, Rubin, Joshua B., Cho, Yoon-Jae, Mclendon, Roger E., Bigner, Darell D., Eberhart, Charles G., Fouladi, Maryam, Wechsler-Reya, Robert J., Faria, Claudia C., Croul, Sidney E., Huang, Annie, Bouffet, Eric, Hawkins, Cynthia E., Dirks, Peter B., Weiss, William A., Schüller, Ulrich, Pollack, Ian F., Rutkowski, Stefan, Meyronet, David, Jouvet, Anne, Fèvre-Montange, Michelle, Jabado, Nada, Perek-Polnik, Marta, Grajkowska, Wieslawa A., Kim, Seung-Ki, Rutka, James T., Malkin, David, Tabori, Uri, Pfister, Stefan M., Korshunov, Andrey, Von Deimling, Andrea, and Taylor, Michael D.
Abstract: Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. © Springer-Verlag Berlin Heidelberg 2013.
Published: 2013

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25 results on '"Faria, Claudia C"'

1. Failure of human rhombic lip differentiation underlies medulloblastoma formation.

2. Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

3. The transcriptional landscape of Shh medulloblastoma.

4. The transcriptional landscape of Shh medulloblastoma.

5. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

6. Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

7. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

8. Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

9. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

10. Heterogeneity within the PF-EPN-B ependymoma subgroup.

11. Intertumoral Heterogeneity within Medulloblastoma Subgroups.

12. Intertumoral Heterogeneity within Medulloblastoma Subgroups

13. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

14. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

15. Divergent clonal selection dominates medulloblastoma at recurrence.

16. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis.

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

18. Divergent clonal selection dominates medulloblastoma at recurrence

19. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

20. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: A retrospective multicohort analysis

21. Molecular subgroups of atypical teratoid rhabdoid tumours in children : an integrated genomic and clinicopathological analysis

22. Cytogenetic prognostication within medulloblastoma subgroups.

23. Cytogenetic prognostication within medulloblastoma subgroups.

24. Cytogenetic prognostication within medulloblastoma subgroups

25. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

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