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1. 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

2. 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

3. Cytogenetic prognostication within medulloblastoma subgroups.

Author

Shih, David, Shih, David, Northcott, Paul, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian, Garzia, Livia, Peacock, John, Mack, Stephen, Wu, Xiaochong, Rolider, Adi, Morrissy, A, Cavalli, Florence, Jones, David, Zitterbart, Karel, Faria, Claudia, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael, Thompson, Reid, Bailey, Simon, Lindsey, Janet, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna, Scherer, Stephen, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey, Rubin, Joshua, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James, Gajjar, Amar, Packer, Roger, Fan, Xing, Muraszko, Karin, Vibhakar, Rajeev, Eberhart, Charles, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian, Rutkowski, Stefan, Pomeroy, Scott, French, Pim, Kloosterhof, Nanne, Kros, Johan, Van Meir, Erwin, Clifford, Steven, Bourdeaut, Franck, Delattre, Olivier, Doz, François, Hawkins, Cynthia, Malkin, David, Grajkowska, Wieslawa, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James, Pfister, Stefan, Taylor, Michael, Gupta, Nalin, Phillips, Joanna, Weiss, William, Liau, Linda, Shih, David, Shih, David, Northcott, Paul, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian, Garzia, Livia, Peacock, John, Mack, Stephen, Wu, Xiaochong, Rolider, Adi, Morrissy, A, Cavalli, Florence, Jones, David, Zitterbart, Karel, Faria, Claudia, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael, Thompson, Reid, Bailey, Simon, Lindsey, Janet, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna, Scherer, Stephen, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey, Rubin, Joshua, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James, Gajjar, Amar, Packer, Roger, Fan, Xing, Muraszko, Karin, Vibhakar, Rajeev, Eberhart, Charles, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian, Rutkowski, Stefan, Pomeroy, Scott, French, Pim, Kloosterhof, Nanne, Kros, Johan, Van Meir, Erwin, Clifford, Steven, Bourdeaut, Franck, Delattre, Olivier, Doz, François, Hawkins, Cynthia, Malkin, David, Grajkowska, Wieslawa, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James, Pfister, Stefan, Taylor, Michael, Gupta, Nalin, Phillips, Joanna, Weiss, William, and Liau, Linda

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.

Published
2014

4. 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

5. 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

6. 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

7. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma.

Author

Dubuc, Adrian M, Dubuc, Adrian M, Remke, Marc, Korshunov, Andrey, Northcott, Paul A, Zhan, Shing H, Mendez-Lago, Maria, Kool, Marcel, Jones, David TW, Unterberger, Alexander, Morrissy, A Sorana, Shih, David, Peacock, John, Ramaswamy, Vijay, Rolider, Adi, Wang, Xin, Witt, Hendrik, Hielscher, Thomas, Hawkins, Cynthia, Vibhakar, Rajeev, Croul, Sidney, Rutka, James T, Weiss, William A, Jones, Steven JM, Eberhart, Charles G, Marra, Marco A, Pfister, Stefan M, Taylor, Michael D, Dubuc, Adrian M, Dubuc, Adrian M, Remke, Marc, Korshunov, Andrey, Northcott, Paul A, Zhan, Shing H, Mendez-Lago, Maria, Kool, Marcel, Jones, David TW, Unterberger, Alexander, Morrissy, A Sorana, Shih, David, Peacock, John, Ramaswamy, Vijay, Rolider, Adi, Wang, Xin, Witt, Hendrik, Hielscher, Thomas, Hawkins, Cynthia, Vibhakar, Rajeev, Croul, Sidney, Rutka, James T, Weiss, William A, Jones, Steven JM, Eberhart, Charles G, Marra, Marco A, Pfister, Stefan M, and Taylor, Michael D

Abstract

Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.

Published
2013

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