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1. The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location

Author

Liu, Ilon, Jiang, Li, Samuelsson, Erik Reinhold, Marco Salas, Sergio, Beck, Alexander, Hack, Olivia A., Jeong, Daeun, Shaw, McKenzie L., Englinger, Bernhard, LaBelle, Jenna, Mire, Hafsa M., Madlener, Sibylle, Mayr, Lisa, Quezada, Michael A., Trissal, Maria, Panditharatna, Eshini, Ernst, Kati J., Vogelzang, Jayne, Gatesman, Taylor A., Halbert, Matthew E., Palova, Hana, Pokorna, Petra, Sterba, Jaroslav, Slaby, Ondrej, Geyeregger, Rene, Diaz, Aaron, Findlay, Izac J., Dun, Matthew D., Resnick, Adam, Suvà, Mario L., Jones, David T. W., Agnihotri, Sameer, Svedlund, Jessica, Koschmann, Carl, Haberler, Christine, Czech, Thomas, Slavc, Irene, Cotter, Jennifer A., Ligon, Keith L., Alexandrescu, Sanda, Yung, W. K. Alfred, Arrillaga-Romany, Isabel, Gojo, Johannes, Monje, Michelle, Nilsson, Mats, Filbin, Mariella G., Liu, Ilon, Jiang, Li, Samuelsson, Erik Reinhold, Marco Salas, Sergio, Beck, Alexander, Hack, Olivia A., Jeong, Daeun, Shaw, McKenzie L., Englinger, Bernhard, LaBelle, Jenna, Mire, Hafsa M., Madlener, Sibylle, Mayr, Lisa, Quezada, Michael A., Trissal, Maria, Panditharatna, Eshini, Ernst, Kati J., Vogelzang, Jayne, Gatesman, Taylor A., Halbert, Matthew E., Palova, Hana, Pokorna, Petra, Sterba, Jaroslav, Slaby, Ondrej, Geyeregger, Rene, Diaz, Aaron, Findlay, Izac J., Dun, Matthew D., Resnick, Adam, Suvà, Mario L., Jones, David T. W., Agnihotri, Sameer, Svedlund, Jessica, Koschmann, Carl, Haberler, Christine, Czech, Thomas, Slavc, Irene, Cotter, Jennifer A., Ligon, Keith L., Alexandrescu, Sanda, Yung, W. K. Alfred, Arrillaga-Romany, Isabel, Gojo, Johannes, Monje, Michelle, Nilsson, Mats, and Filbin, Mariella G.

Abstract

Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.

Published
2022
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2. The state of neuro-oncology during the COVID-19 pandemic:A worldwide assessment

Author

Mrugala, MacIej M., Ostrom, Quinn T., Pressley, Shelley M., Taylor, Jennie W., Thomas, Alissa A., Wefel, Jeffrey S., Coven, Scott L., Acquaye, Alvina A., Haynes, Chas, Agnihotri, Sameer, Lim, Michael, Peters, Katherine B., Sulman, Erik P., Salcido, Joanne T., Butowski, Nicholas A., Hervey-Jumper, Shawn, Mansouri, Alireza, Oliver, Kathy R., Porter, Alyx B., Nassiri, Farshad, Schiff, David, Dunbar, Erin M., Hegi, Monika E., Armstrong, Terri S., Van Den Bent, Martin J., Chang, Susan M., Zadeh, Gelareh, Chheda, Milan G., Mrugala, MacIej M., Ostrom, Quinn T., Pressley, Shelley M., Taylor, Jennie W., Thomas, Alissa A., Wefel, Jeffrey S., Coven, Scott L., Acquaye, Alvina A., Haynes, Chas, Agnihotri, Sameer, Lim, Michael, Peters, Katherine B., Sulman, Erik P., Salcido, Joanne T., Butowski, Nicholas A., Hervey-Jumper, Shawn, Mansouri, Alireza, Oliver, Kathy R., Porter, Alyx B., Nassiri, Farshad, Schiff, David, Dunbar, Erin M., Hegi, Monika E., Armstrong, Terri S., Van Den Bent, Martin J., Chang, Susan M., Zadeh, Gelareh, and Chheda, Milan G.

Abstract

Background:It remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts. Methods:We performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24-May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients. Results:Of 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners. Conclusions:The pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of

Published
2021

3. Impact of acute lymphoblastic leukemia induction therapy:findings from metabolomics on non-fasted plasma samples from a biorepository

Author

Saito, Toshie, Wei, Yue, Wen, Li, Srinivasan, Chaitanya, Wolthers, Benjamin O., Tsai, Cheng Yu, Harris, Marian H., Stevenson, Kristen, Byersdorfer, Craig, Oparaji, Judy April, Fernandez, Christian, Mukherjee, Amitava, Abu-El-Haija, Maisam, Agnihotri, Sameer, Schmiegelow, Kjeld, Showalter, Megan R., Fogle, Paul W., McCulloch, Scott, Contrepois, Kevin, Silverman, Lewis B., Ding, Ying, Husain, Sohail Z., Saito, Toshie, Wei, Yue, Wen, Li, Srinivasan, Chaitanya, Wolthers, Benjamin O., Tsai, Cheng Yu, Harris, Marian H., Stevenson, Kristen, Byersdorfer, Craig, Oparaji, Judy April, Fernandez, Christian, Mukherjee, Amitava, Abu-El-Haija, Maisam, Agnihotri, Sameer, Schmiegelow, Kjeld, Showalter, Megan R., Fogle, Paul W., McCulloch, Scott, Contrepois, Kevin, Silverman, Lewis B., Ding, Ying, and Husain, Sohail Z.

Abstract

Introduction: Acute lymphoblastic leukemia (ALL) is among the most common cancers in children. With improvements in combination chemotherapy regimens, the overall survival has increased to over 90%. However, the current challenge is to mitigate adverse events resulting from the complex therapy. Several chemotherapies intercept cancer metabolism, but little is known about their collective role in altering host metabolism. Objectives: We profiled the metabolomic changes in plasma of ALL patients initial- and post- induction therapy. Methods: We exploited a biorepository of non-fasted plasma samples derived from the Dana Farber Cancer Institute ALL Consortium; these samples were obtained from 50 ALL patients initial- and post-induction therapy. Plasma metabolites and complex lipids were analyzed by high resolution tandem mass spectrometry and differential mobility tandem mass spectrometry. Data were analyzed using a covariate-adjusted regression model with multiplicity adjustment. Pathway enrichment analysis and co-expression network analysis were performed to identify unique clusters of molecules. Results: More than 1200 metabolites and complex lipids were identified in the total of global metabolomics and lipidomics platforms. Over 20% of those molecules were significantly altered. In the pathway enrichment analysis, lipids, particularly phosphatidylethanolamines (PEs), were identified. Network analysis indicated that the bioactive fatty acids, docosahexaenoic acid (DHA)-containing (22:6) triacylglycerols (TAGs), were decreased in the post-induction therapy. Conclusion: Metabolomic profiling in ALL patients revealed a large number of alterations following induction chemotherapy. In particular, lipid metabolism was substantially altered. The changes in metabolites and complex lipids following induction therapy could provide insight into the adverse events experienced by ALL patients.

Published
2021

4. Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas.

Author

Müller, Sören, Müller, Sören, Agnihotri, Sameer, Shoger, Karsen E, Myers, Max I, Smith, Nicholas, Chaparala, Srilakshmi, Villanueva, Clarence R, Chattopadhyay, Ansuman, Lee, Adrian V, Butterfield, Lisa H, Diaz, Aaron, Okada, Hideho, Pollack, Ian F, Kohanbash, Gary, Müller, Sören, Müller, Sören, Agnihotri, Sameer, Shoger, Karsen E, Myers, Max I, Smith, Nicholas, Chaparala, Srilakshmi, Villanueva, Clarence R, Chattopadhyay, Ansuman, Lee, Adrian V, Butterfield, Lisa H, Diaz, Aaron, Okada, Hideho, Pollack, Ian F, and Kohanbash, Gary

Abstract

Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns.

Published
2018

5. 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

6. 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

7. The genomic landscape of schwannoma

Author

Agnihotri, Sameer, Jalali, Shahrzad, Wilson, Mark R., Danesh, Arnavaz, Li, Mira, Klironomos, George, Krieger, Jonathan R., Mansouri, Alireza, Khan, Osaama, Mamatjan, Yasin, Landon-Brace, Natalie, Tung, Takyee, Dowar, Mark, Li, Tiantian, Bruce, Jeffrey P., Burrell, Kelly E., Tonge, Peter D., Alamsahebpour, Amir, Krischek, Boris, Agarwalla, Pankaj Kumar, Bi, Wenya Linda, Dunn, Ian F., Beroukhim, Rameen, Fehlings, Michael G., Bril, Vera, Pagnotta, Stefano M., Iavarone, Antonio, Pugh, Trevor J., Aldape, Kenneth D., Zadeh, Gelareh, Agnihotri, Sameer, Jalali, Shahrzad, Wilson, Mark R., Danesh, Arnavaz, Li, Mira, Klironomos, George, Krieger, Jonathan R., Mansouri, Alireza, Khan, Osaama, Mamatjan, Yasin, Landon-Brace, Natalie, Tung, Takyee, Dowar, Mark, Li, Tiantian, Bruce, Jeffrey P., Burrell, Kelly E., Tonge, Peter D., Alamsahebpour, Amir, Krischek, Boris, Agarwalla, Pankaj Kumar, Bi, Wenya Linda, Dunn, Ian F., Beroukhim, Rameen, Fehlings, Michael G., Bril, Vera, Pagnotta, Stefano M., Iavarone, Antonio, Pugh, Trevor J., Aldape, Kenneth D., and Zadeh, Gelareh

Abstract

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

Published
2016

8. The genomic landscape of schwannoma

Author

Agnihotri, Sameer, Jalali, Shahrzad, Wilson, Mark R., Danesh, Arnavaz, Li, Mira, Klironomos, George, Krieger, Jonathan R., Mansouri, Alireza, Khan, Osaama, Mamatjan, Yasin, Landon-Brace, Natalie, Tung, Takyee, Dowar, Mark, Li, Tiantian, Bruce, Jeffrey P., Burrell, Kelly E., Tonge, Peter D., Alamsahebpour, Amir, Krischek, Boris, Agarwalla, Pankaj Kumar, Bi, Wenya Linda, Dunn, Ian F., Beroukhim, Rameen, Fehlings, Michael G., Bril, Vera, Pagnotta, Stefano M., Iavarone, Antonio, Pugh, Trevor J., Aldape, Kenneth D., Zadeh, Gelareh, Agnihotri, Sameer, Jalali, Shahrzad, Wilson, Mark R., Danesh, Arnavaz, Li, Mira, Klironomos, George, Krieger, Jonathan R., Mansouri, Alireza, Khan, Osaama, Mamatjan, Yasin, Landon-Brace, Natalie, Tung, Takyee, Dowar, Mark, Li, Tiantian, Bruce, Jeffrey P., Burrell, Kelly E., Tonge, Peter D., Alamsahebpour, Amir, Krischek, Boris, Agarwalla, Pankaj Kumar, Bi, Wenya Linda, Dunn, Ian F., Beroukhim, Rameen, Fehlings, Michael G., Bril, Vera, Pagnotta, Stefano M., Iavarone, Antonio, Pugh, Trevor J., Aldape, Kenneth D., and Zadeh, Gelareh

Abstract

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

Published
2016

10. Therapeutic targeting based on gene-expression profiling in vestibular schwannomas Response

Author

Zadeh, Gelareh, Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, Krischek, Boris, Zadeh, Gelareh, Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, and Krischek, Boris

Published
2014

11. Gene-expression profiling elucidates molecular signaling networks that can be therapeutically targeted in vestibular schwannoma

Author

Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, Zadeh, Gelareh, Krischek, Boris, Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, Zadeh, Gelareh, and Krischek, Boris

Abstract

Object. Vestibular schwannomas (VS) are common benign tumors of the vestibular nerve that cause significant morbidity. The current treatment strategies for VS include surgery or radiation, with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown. Methods. In this study the authors performed gene-expression profiling of 49 schwannomas and 7 normal control vestibular nerves to identify tumor-specific gene-expression patterns. They also interrogated whether schwannomas comprise several molecular subtypes using several transcription-based clustering strategies. The authors also performed in vitro experiments testing therapeutic inhibitors of over-activated pathways in a schwannoma cell line, namely the PI3K/AKT/mTOR pathway. Results. The authors identified over 4000 differentially expressed genes between controls and schwannomas with network analysis, uncovering proliferation and anti-apoptotic pathways previously not implicated in VS. Furthermore, using several distinct clustering technologies, they could not reproducibly identify distinct VS subtypes or significant differences between sporadic and germline NF2-associated schwannomas, suggesting that they are highly similar entities. The authors identified overexpression of PI3K/AKT/mTOR signaling networks in their gene-expression study and evaluated this pathway for therapeutic targeting. Testing the compounds BEZ235 and PKI-587, both novel dual inhibitors of PI3K and mTOR, attenuated tumor growth in a preclinical cell line model of schwannoma (HEI-293). In vitro findings demonstrated that pharmacological inhibition of the PI3K/AKT/mTOR pathway with next-generation compounds led to decreased cell viability and increased cell death. Conclusions. These findings implicate aberrant activation of the PI3K/AKT/mTOR pathway as a molecular mechanism of pathogenesis in VS and suggest inhibition of this pathway as a potential treatment strat

Published
2014

12. Gene-expression profiling elucidates molecular signaling networks that can be therapeutically targeted in vestibular schwannoma

Author

Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, Zadeh, Gelareh, Krischek, Boris, Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, Zadeh, Gelareh, and Krischek, Boris

Abstract

Object. Vestibular schwannomas (VS) are common benign tumors of the vestibular nerve that cause significant morbidity. The current treatment strategies for VS include surgery or radiation, with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown. Methods. In this study the authors performed gene-expression profiling of 49 schwannomas and 7 normal control vestibular nerves to identify tumor-specific gene-expression patterns. They also interrogated whether schwannomas comprise several molecular subtypes using several transcription-based clustering strategies. The authors also performed in vitro experiments testing therapeutic inhibitors of over-activated pathways in a schwannoma cell line, namely the PI3K/AKT/mTOR pathway. Results. The authors identified over 4000 differentially expressed genes between controls and schwannomas with network analysis, uncovering proliferation and anti-apoptotic pathways previously not implicated in VS. Furthermore, using several distinct clustering technologies, they could not reproducibly identify distinct VS subtypes or significant differences between sporadic and germline NF2-associated schwannomas, suggesting that they are highly similar entities. The authors identified overexpression of PI3K/AKT/mTOR signaling networks in their gene-expression study and evaluated this pathway for therapeutic targeting. Testing the compounds BEZ235 and PKI-587, both novel dual inhibitors of PI3K and mTOR, attenuated tumor growth in a preclinical cell line model of schwannoma (HEI-293). In vitro findings demonstrated that pharmacological inhibition of the PI3K/AKT/mTOR pathway with next-generation compounds led to decreased cell viability and increased cell death. Conclusions. These findings implicate aberrant activation of the PI3K/AKT/mTOR pathway as a molecular mechanism of pathogenesis in VS and suggest inhibition of this pathway as a potential treatment strat

Published
2014

14. Therapeutic targeting based on gene-expression profiling in vestibular schwannomas Response

Author

Zadeh, Gelareh, Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, Krischek, Boris, Zadeh, Gelareh, Agnihotri, Sameer, Gugel, Isabel, Remke, Marc, Bornemann, Antje, Pantazis, Georgios, Mack, Stephen C., Shih, David, Singh, Sanjay K., Sabha, Nesrin, Taylor, Michael D., Tatagiba, Marcos, and Krischek, Boris

Published
2014

15. 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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