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1. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (cns) tumors and tropomyosin receptor kinase (trk) fusion.

Author: Lamoureux A.-A., Fisher M., Lemelle L., Pfaff E., Kramm C., De Wilde B., Kazanowska B., Hutter C., Pfister S.M., Sturm D., Jones D., Orbach D., Pierron G., Raskin S., Drilon A., Diamond E., Harada G., Zapotocky M., Ellezam B., Weil A.G., Venne D., Barritault M., Leblond P., Coltin H., Hammad R., Tabori U., Hawkins C., Hansford J.R., Meyran D., Erker C., McFadden K., Sato M., Gottardo N.G., Dholaria H., Noroxe D.S., Goto H., Ziegler D.S., Lin F.Y., Parsons D.W., Lindsay H., Wong T.-T., Liu Y.-L., Wu K.-S., Franson A.F., Hwang E., Aguilar-Bonilla A., Cheng S., Cacciotti C., Massimino M., Schiavello E., Wood P., Hoffman L.M., Cappellano A., Lassaletta A., Van Damme A., Llort A., Gerber N.U., Ceruso M.S., Bendel A.E., Skrypek M., Hamideh D., Mushtaq N., Walter A., Jabado N., Alsahlawi A., Farmer J.-P., Abadi C.C., Mueller S., Mazewski C., Aguilera D., Robison N., O'Halloran K., Abbou S., Berlanga P., Geoerger B., Ora I., Moertel C.L., Razis E.D., Vernadou A., Doz F., Laetsch T.W., Perreault S., Lamoureux A.-A., Fisher M., Lemelle L., Pfaff E., Kramm C., De Wilde B., Kazanowska B., Hutter C., Pfister S.M., Sturm D., Jones D., Orbach D., Pierron G., Raskin S., Drilon A., Diamond E., Harada G., Zapotocky M., Ellezam B., Weil A.G., Venne D., Barritault M., Leblond P., Coltin H., Hammad R., Tabori U., Hawkins C., Hansford J.R., Meyran D., Erker C., McFadden K., Sato M., Gottardo N.G., Dholaria H., Noroxe D.S., Goto H., Ziegler D.S., Lin F.Y., Parsons D.W., Lindsay H., Wong T.-T., Liu Y.-L., Wu K.-S., Franson A.F., Hwang E., Aguilar-Bonilla A., Cheng S., Cacciotti C., Massimino M., Schiavello E., Wood P., Hoffman L.M., Cappellano A., Lassaletta A., Van Damme A., Llort A., Gerber N.U., Ceruso M.S., Bendel A.E., Skrypek M., Hamideh D., Mushtaq N., Walter A., Jabado N., Alsahlawi A., Farmer J.-P., Abadi C.C., Mueller S., Mazewski C., Aguilera D., Robison N., O'Halloran K., Abbou S., Berlanga P., Geoerger B., Ora I., Moertel C.L., Razis E.D., Vernadou A., Doz F., Laetsch T.W., and Perreault S.
Abstract: BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHOD(S): We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULT(S): Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0-17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSION(S): We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.
Published: 2022

2. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author: Das, A, Sudhaman, S, Morgenstern, D, Coblentz, A, Chung, J, Stone, SC, Alsafwani, N, Liu, ZA, Abu Al Karsaneh, O, Soleimani, S, Ladany, H, Chen, D, Zatzman, M, Cabric, V, Nobre, L, Bianchi, V, Edwards, M, Nahum, LCS, Ercan, AB, Nabbi, A, Constantini, S, Dvir, R, Yalon-Oren, M, Campino, GA, Caspi, S, Larouche, V, Reddy, A, Osborn, M, Mason, G, Lindhorst, S, Bronsema, A, Magimairajan, V, Opocher, E, De Mola, RL, Sabel, M, Frojd, C, Sumerauer, D, Samuel, D, Cole, K, Chiaravalli, S, Massimino, M, Tomboc, P, Ziegler, DS, George, B, Van Damme, A, Hijiya, N, Gass, D, McGee, RB, Mordechai, O, Bowers, DC, Laetsch, TW, Lossos, A, Blumenthal, DT, Sarosiek, T, Yen, LY, Knipstein, J, Bendel, A, Hoffman, LM, Luna-Fineman, S, Zimmermann, S, Scheers, I, Nichols, KE, Zapotocky, M, Hansford, JR, Maris, JM, Dirks, P, Taylor, MD, Kulkarni, A, Shroff, M, Tsang, DS, Villani, A, Xu, W, Aronson, M, Durno, C, Shlien, A, Malkin, D, Getz, G, Maruvka, YE, Ohashi, PS, Hawkins, C, Pugh, TJ, Bouffet, E, Tabori, U, Das, A, Sudhaman, S, Morgenstern, D, Coblentz, A, Chung, J, Stone, SC, Alsafwani, N, Liu, ZA, Abu Al Karsaneh, O, Soleimani, S, Ladany, H, Chen, D, Zatzman, M, Cabric, V, Nobre, L, Bianchi, V, Edwards, M, Nahum, LCS, Ercan, AB, Nabbi, A, Constantini, S, Dvir, R, Yalon-Oren, M, Campino, GA, Caspi, S, Larouche, V, Reddy, A, Osborn, M, Mason, G, Lindhorst, S, Bronsema, A, Magimairajan, V, Opocher, E, De Mola, RL, Sabel, M, Frojd, C, Sumerauer, D, Samuel, D, Cole, K, Chiaravalli, S, Massimino, M, Tomboc, P, Ziegler, DS, George, B, Van Damme, A, Hijiya, N, Gass, D, McGee, RB, Mordechai, O, Bowers, DC, Laetsch, TW, Lossos, A, Blumenthal, DT, Sarosiek, T, Yen, LY, Knipstein, J, Bendel, A, Hoffman, LM, Luna-Fineman, S, Zimmermann, S, Scheers, I, Nichols, KE, Zapotocky, M, Hansford, JR, Maris, JM, Dirks, P, Taylor, MD, Kulkarni, A, Shroff, M, Tsang, DS, Villani, A, Xu, W, Aronson, M, Durno, C, Shlien, A, Malkin, D, Getz, G, Maruvka, YE, Ohashi, PS, Hawkins, C, Pugh, TJ, Bouffet, E, and Tabori, U
Abstract: Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.
Published: 2022

3. HGG-11. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (CNS) tumors and tropomyosin receptor kinase (TRK) fusion.

Author: Lamoureux, A-A, Fisher, M, Lemelle, L, Pfaff, E, Kramm, C, De Wilde, B, Kazanowska, B, Hutter, C, Pfister, SM, Sturm, D, Jones, D, Orbach, D, Pierron, G, Raskin, S, Drilon, A, Diamond, E, Harada, G, Zapotocky, M, Ellezam, B, Weil, AG, Venne, D, Barritault, M, Leblond, P, Coltin, H, Hammad, R, Tabori, U, Hawkins, C, Hansford, JR, Meyran, D, Erker, C, McFadden, K, Sato, M, Gottardo, NG, Dholaria, H, Nørøxe, DS, Goto, H, Ziegler, DS, Lin, FY, Parsons, DW, Lindsay, H, Wong, T-T, Liu, Y-L, Wu, K-S, Franson, AF, Hwang, E, Aguilar-Bonilla, A, Cheng, S, Cacciotti, C, Massimino, M, Schiavello, E, Wood, P, Hoffman, LM, Cappellano, A, Lassaletta, A, Van Damme, A, Llort, A, Gerber, NU, Ceruso, MS, Bendel, AE, Skrypek, M, Hamideh, D, Mushtaq, N, Walter, A, Jabado, N, Alsahlawi, A, Farmer, J-P, Abadi, CC, Mueller, S, Mazewski, C, Aguilera, D, Robison, N, O’Halloran, K, Abbou, S, Berlanga, P, Geoerger, B, Øra, I, Moertel, CL, Razis, ED, Vernadou, A, Doz, F, Laetsch, TW, Perreault, S, Lamoureux, A-A, Fisher, M, Lemelle, L, Pfaff, E, Kramm, C, De Wilde, B, Kazanowska, B, Hutter, C, Pfister, SM, Sturm, D, Jones, D, Orbach, D, Pierron, G, Raskin, S, Drilon, A, Diamond, E, Harada, G, Zapotocky, M, Ellezam, B, Weil, AG, Venne, D, Barritault, M, Leblond, P, Coltin, H, Hammad, R, Tabori, U, Hawkins, C, Hansford, JR, Meyran, D, Erker, C, McFadden, K, Sato, M, Gottardo, NG, Dholaria, H, Nørøxe, DS, Goto, H, Ziegler, DS, Lin, FY, Parsons, DW, Lindsay, H, Wong, T-T, Liu, Y-L, Wu, K-S, Franson, AF, Hwang, E, Aguilar-Bonilla, A, Cheng, S, Cacciotti, C, Massimino, M, Schiavello, E, Wood, P, Hoffman, LM, Cappellano, A, Lassaletta, A, Van Damme, A, Llort, A, Gerber, NU, Ceruso, MS, Bendel, AE, Skrypek, M, Hamideh, D, Mushtaq, N, Walter, A, Jabado, N, Alsahlawi, A, Farmer, J-P, Abadi, CC, Mueller, S, Mazewski, C, Aguilera, D, Robison, N, O’Halloran, K, Abbou, S, Berlanga, P, Geoerger, B, Øra, I, Moertel, CL, Razis, ED, Vernadou, A, Doz, F, Laetsch, TW, and Perreault, S
Abstract: BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHODS: We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULTS: Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0–17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSIONS: We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.
Published: 2022

4. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

Author: Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, Northcott, PA, Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, and Northcott, PA
Abstract: PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular ta
Published: 2021

5. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author: Durno, C, Ercan, AB, Bianchi, V, Edwards, M, Aronson, M, Galati, M, Atenafu, EG, Abebe-Campino, G, Al-Battashi, A, Alharbi, M, Azad, VF, Baris, HN, Basel, D, Bedgood, R, Bendel, A, Ben-Shachar, S, Blumenthal, DT, Blundell, M, Bornhorst, M, Bronsema, A, Cairney, E, Rhode, S, Caspi, S, Chamdin, A, Chiaravalli, S, Constantini, S, Crooks, B, Das, A, Dvir, R, Farah, R, Foulkes, WD, Frenkel, Z, Gallinger, B, Gardner, S, Gass, D, Ghalibafian, M, Gilpin, C, Goldberg, Y, Goudie, C, Hamid, SA, Hampel, H, Hansford, JR, Harlos, C, Hijiya, N, Hsu, S, Kamihara, J, Kebudi, R, Knipstein, J, Koschmann, C, Kratz, C, Larouche, V, Lassaletta, A, Lindhorst, S, Ling, SC, Link, MP, De Mola, RL, Luiten, R, Lurye, M, Maciaszek, JL, MagimairajanIssai, V, Maher, OM, Massimino, M, McGee, RB, Mushtaq, N, Mason, G, Newmark, M, Nicholas, G, Nichols, KE, Nicolaides, T, Opocher, E, Osborn, M, Oshrine, B, Pearlman, R, Pettee, D, Rapp, J, Rashid, M, Reddy, A, Reichman, L, Remke, M, Robbins, G, Roy, S, Sabel, M, Samuel, D, Scheers, I, Schneider, KW, Sen, S, Stearns, D, Sumerauer, D, Swallow, C, Taylor, L, Thomas, G, Toledano, H, Tomboc, P, Van Damme, A, Winer, I, Yalon, M, Yen, LY, Zapotocky, M, Zelcer, S, Ziegler, DS, Zimmermann, S, Hawkins, C, Malkin, D, Bouffet, E, Villani, A, Tabori, U, Durno, C, Ercan, AB, Bianchi, V, Edwards, M, Aronson, M, Galati, M, Atenafu, EG, Abebe-Campino, G, Al-Battashi, A, Alharbi, M, Azad, VF, Baris, HN, Basel, D, Bedgood, R, Bendel, A, Ben-Shachar, S, Blumenthal, DT, Blundell, M, Bornhorst, M, Bronsema, A, Cairney, E, Rhode, S, Caspi, S, Chamdin, A, Chiaravalli, S, Constantini, S, Crooks, B, Das, A, Dvir, R, Farah, R, Foulkes, WD, Frenkel, Z, Gallinger, B, Gardner, S, Gass, D, Ghalibafian, M, Gilpin, C, Goldberg, Y, Goudie, C, Hamid, SA, Hampel, H, Hansford, JR, Harlos, C, Hijiya, N, Hsu, S, Kamihara, J, Kebudi, R, Knipstein, J, Koschmann, C, Kratz, C, Larouche, V, Lassaletta, A, Lindhorst, S, Ling, SC, Link, MP, De Mola, RL, Luiten, R, Lurye, M, Maciaszek, JL, MagimairajanIssai, V, Maher, OM, Massimino, M, McGee, RB, Mushtaq, N, Mason, G, Newmark, M, Nicholas, G, Nichols, KE, Nicolaides, T, Opocher, E, Osborn, M, Oshrine, B, Pearlman, R, Pettee, D, Rapp, J, Rashid, M, Reddy, A, Reichman, L, Remke, M, Robbins, G, Roy, S, Sabel, M, Samuel, D, Scheers, I, Schneider, KW, Sen, S, Stearns, D, Sumerauer, D, Swallow, C, Taylor, L, Thomas, G, Toledano, H, Tomboc, P, Van Damme, A, Winer, I, Yalon, M, Yen, LY, Zapotocky, M, Zelcer, S, Ziegler, DS, Zimmermann, S, Hawkins, C, Malkin, D, Bouffet, E, Villani, A, and Tabori, U
Abstract: PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
Published: 2021

6. Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

Author: Khan, S, Solano-Paez, P, Suwal, T, Lu, M, Al-Karmi, S, Ho, B, Mumal, I, Shago, M, Hoffman, LM, Dodgshun, A, Nobusawa, S, Tabori, U, Bartels, U, Ziegler, DS, Hansford, JR, Ramaswamy, V, Hawkins, C, Dufour, C, André, N, Bouffet, E, Huang, A, Rare Brain Tumor Registry, Khan, S, Solano-Paez, P, Suwal, T, Lu, M, Al-Karmi, S, Ho, B, Mumal, I, Shago, M, Hoffman, LM, Dodgshun, A, Nobusawa, S, Tabori, U, Bartels, U, Ziegler, DS, Hansford, JR, Ramaswamy, V, Hawkins, C, Dufour, C, André, N, Bouffet, E, Huang, A, and Rare Brain Tumor Registry
Abstract: BACKGROUND: Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease. METHODS: Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors. FINDINGS: 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18-36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47-68) at 6 months and 31% (21-42) at 2 years; overall survival was 29% (20-38) at 2 years an
Published: 2021

7. Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

Author: Khan, S, Solano-Paez, P, Suwal, T, Lu, M, Al-Karmi, S, Ho, B, Mumal, I, Shago, M, Hoffman, LM, Dodgshun, A, Nobusawa, S, Tabori, U, Bartels, U, Ziegler, DS, Hansford, JR, Ramaswamy, V, Hawkins, C, Dufour, C, André, N, Bouffet, E, Huang, A, Rare Brain Tumor Registry, Khan, S, Solano-Paez, P, Suwal, T, Lu, M, Al-Karmi, S, Ho, B, Mumal, I, Shago, M, Hoffman, LM, Dodgshun, A, Nobusawa, S, Tabori, U, Bartels, U, Ziegler, DS, Hansford, JR, Ramaswamy, V, Hawkins, C, Dufour, C, André, N, Bouffet, E, Huang, A, and Rare Brain Tumor Registry
Abstract: BACKGROUND: Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease. METHODS: Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors. FINDINGS: 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18-36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47-68) at 6 months and 31% (21-42) at 2 years; overall survival was 29% (20-38) at 2 years an
Published: 2021

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

Author: Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, Ramaswamy, V, Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, and Ramaswamy, V
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

9. HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS

Author: Dodgshun, A, Fukuoka, K, Edwards, M, Bianchi, V, Sexton-Oates, A, Larouche, V, Magimairajan, V, Lindhorst, S, Yalon, M, Mason, G, Crooks, B, Constantini, S, Massimino, M, Chiaravalli, S, Ramdas, J, Mason, W, Shamvil, A, Farah, R, Van Damme, A, Opocher, E, Hamid, SA, Ziegler, D, Samuel, D, Cole, KA, Tomboc, P, Stearns, D, Thomas, G, Lossos, A, Sullivan, M, Hansford, JR, Jones, D, Mackay, A, Jones, C, Ramaswamy, V, Hawkins, C, Bouffet, E, Tabori, U, Dodgshun, A, Fukuoka, K, Edwards, M, Bianchi, V, Sexton-Oates, A, Larouche, V, Magimairajan, V, Lindhorst, S, Yalon, M, Mason, G, Crooks, B, Constantini, S, Massimino, M, Chiaravalli, S, Ramdas, J, Mason, W, Shamvil, A, Farah, R, Van Damme, A, Opocher, E, Hamid, SA, Ziegler, D, Samuel, D, Cole, KA, Tomboc, P, Stearns, D, Thomas, G, Lossos, A, Sullivan, M, Hansford, JR, Jones, D, Mackay, A, Jones, C, Ramaswamy, V, Hawkins, C, Bouffet, E, and Tabori, U
Abstract: Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.
Published: 2020

10. NASPGHAN Annual Meeting Abstracts

Author: UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, Tabori, U, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, and Tabori, U
Abstract: Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome causing intestinal polyposis and a high risk of early onset gastrointestinal, brain, and hematological cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. Aim: Our aim was to determine if surveillance affects outcome. The primary outcome measure was overall survival. The secondary outcome measure was detection of new cancers. Methods: Patients referred to the International Replication Repair Consortium undergo genetic testing to confirm CMMRD. All individuals were diagnosed with CMMRD through diagnostic criteria by the genetic counsellor at the consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging studies was recommended and initiated internationally on Jan 1, 2012. Protocol included upper endoscopy, colonoscopy, video capsule endoscopy and/or magnetic resonance enterography, and brain MRI. Whole-body MRI was recommended as of Jan 1, 2018. Surveillance questionnaire was sent to the responsible physician with diagnostic fields completed by the registry coordinator as a double check of reliability. Survival analyses was completed using an as-treated approach. Results: Cancer and surveillance data was collected from 64 (50%) of 127 CMMRD individuals registered in the Consortium from 41 countries. There were 114 tumours reported in 60 patients including 55 brain, 28 gastrointestinal (GI), 17 hematological and 14 other malignancies. Surveillance data was available on 110 cancers; 16 were incidental cancers, 68 were symptomatic and 26 were discovered through surveillance. Surveillance identified 13 GI cancers, 11 brain, and 2 hematological malignancies. The gastrointestinal cancers included 5 colorectal, 7 small bowel, and one gastric. Four patients were unaffected. Five-year overall survival was 95% for tumors discovered by surveillance, comp
Published: 2019

11. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Author: Guerreiro Stucklin, AS, Ryall, S, Fukuoka, K, Zapotocky, M, Lassaletta, A, Li, C, Bridge, T, Kim, B, Arnoldo, A, Kowalski, PE, Zhong, Y, Johnson, M, Ramani, AK, Siddaway, R, Nobre, LF, de Antonellis, P, Dunham, C, Cheng, S, Boué, DR, Finlay, JL, Coven, SL, de Prada, I, Perez-Somarriba, M, Faria, CC, Grotzer, MA, Rushing, E, Sumerauer, D, Zamecnik, J, Krskova, L, Garcia Ariza, M, Cruz, O, Morales La Madrid, A, Solano, P, Terashima, K, Nakano, Y, Ichimura, K, Nagane, M, Sakamoto, H, Gil-da-Costa, MJ, Silva, R, Johnston, DL, Michaud, J, Wilson, B, van Landeghem, FKH, Oviedo, A, McNeely, PD, Crooks, B, Fried, I, Zhukova, N, Hansford, JR, Nageswararao, A, Garzia, L, Shago, M, Brudno, M, Irwin, MS, Bartels, U, Ramaswamy, V, Bouffet, E, Taylor, MD, Tabori, U, Hawkins, C, Guerreiro Stucklin, AS, Ryall, S, Fukuoka, K, Zapotocky, M, Lassaletta, A, Li, C, Bridge, T, Kim, B, Arnoldo, A, Kowalski, PE, Zhong, Y, Johnson, M, Ramani, AK, Siddaway, R, Nobre, LF, de Antonellis, P, Dunham, C, Cheng, S, Boué, DR, Finlay, JL, Coven, SL, de Prada, I, Perez-Somarriba, M, Faria, CC, Grotzer, MA, Rushing, E, Sumerauer, D, Zamecnik, J, Krskova, L, Garcia Ariza, M, Cruz, O, Morales La Madrid, A, Solano, P, Terashima, K, Nakano, Y, Ichimura, K, Nagane, M, Sakamoto, H, Gil-da-Costa, MJ, Silva, R, Johnston, DL, Michaud, J, Wilson, B, van Landeghem, FKH, Oviedo, A, McNeely, PD, Crooks, B, Fried, I, Zhukova, N, Hansford, JR, Nageswararao, A, Garzia, L, Shago, M, Brudno, M, Irwin, MS, Bartels, U, Ramaswamy, V, Bouffet, E, Taylor, MD, Tabori, U, and Hawkins, C
Abstract: Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
Published: 2019

12. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

Author: Achatz, M.I., Porter, C.C., Brugieres, L., Druker, H., Frebourg, T., Foulkes, W.D., Kratz, C.P., Kuiper, R.P., Hansford, J.R., Hernandez, H.S., Nathanson, K.L., Kohlmann, W.K., Doros, L., Onel, K., Schneider, K.W, Scollon, S.R., Tabori, U., Tomlinson, G.E., Evans, D.G., Plon, S.E., Achatz, M.I., Porter, C.C., Brugieres, L., Druker, H., Frebourg, T., Foulkes, W.D., Kratz, C.P., Kuiper, R.P., Hansford, J.R., Hernandez, H.S., Nathanson, K.L., Kohlmann, W.K., Doros, L., Onel, K., Schneider, K.W, Scollon, S.R., Tabori, U., Tomlinson, G.E., Evans, D.G., and Plon, S.E.
Abstract: Item does not contain fulltext, Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz-Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107-e14. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Published: 2017

13. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

Author: Pajtler, KW, Mack, SC, Ramaswamy, V, Smith, CA, Witt, H, Smith, A, Hansford, JR, von Hoff, K, Wright, KD, Hwang, E, Frappaz, D, Kanemura, Y, Massimino, M, Faure-Conter, C, Modena, P, Tabori, U, Warren, KE, Holland, EC, Ichimura, K, Giangaspero, F, Castel, D, von Deimling, A, Kool, M, Dirks, PB, Grundy, RG, Foreman, NK, Gajjar, A, Korshunov, A, Finlay, J, Gilbertson, RJ, Ellison, DW, Aldape, KD, Merchant, TE, Bouffet, E, Pfister, SM, Taylor, MD, Pajtler, KW, Mack, SC, Ramaswamy, V, Smith, CA, Witt, H, Smith, A, Hansford, JR, von Hoff, K, Wright, KD, Hwang, E, Frappaz, D, Kanemura, Y, Massimino, M, Faure-Conter, C, Modena, P, Tabori, U, Warren, KE, Holland, EC, Ichimura, K, Giangaspero, F, Castel, D, von Deimling, A, Kool, M, Dirks, PB, Grundy, RG, Foreman, NK, Gajjar, A, Korshunov, A, Finlay, J, Gilbertson, RJ, Ellison, DW, Aldape, KD, Merchant, TE, Bouffet, E, Pfister, SM, and Taylor, MD
Abstract: Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.
Published: 2017

14. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

Author: Achatz, M.I., Porter, C.C., Brugieres, L., Druker, H., Frebourg, T., Foulkes, W.D., Kratz, C.P., Kuiper, R.P., Hansford, J.R., Hernandez, H.S., Nathanson, K.L., Kohlmann, W.K., Doros, L., Onel, K., Schneider, K.W, Scollon, S.R., Tabori, U., Tomlinson, G.E., Evans, D.G., Plon, S.E., Achatz, M.I., Porter, C.C., Brugieres, L., Druker, H., Frebourg, T., Foulkes, W.D., Kratz, C.P., Kuiper, R.P., Hansford, J.R., Hernandez, H.S., Nathanson, K.L., Kohlmann, W.K., Doros, L., Onel, K., Schneider, K.W, Scollon, S.R., Tabori, U., Tomlinson, G.E., Evans, D.G., and Plon, S.E.
Abstract: Item does not contain fulltext, Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz-Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107-e14. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Published: 2017

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

Author: Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., Taylor, M.D. (Michael), Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., and Taylor, M.D. (Michael)
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 cm2 tumour remaining), or sub-total resection (≥1·5 cm2 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. 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 mod
Published: 2016
Full Text: View/download PDF

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

Author: Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., Taylor, M.D. (Michael), Thompson, E.M. (Eric M.), Hielscher, T. (Thomas), Bouffet, E. (Eric), Remke, M. (Marc), Luu, P. (Phan), Gururangan, S. (Sridharan), McLendon, R.E. (Roger E.), Bigner, D.D. (Darell), Lipp, E.S. (Eric S.), Perreault, S. (Sebastien), Cho, Y.-J. (Yoon-Jae), Grant, G. (Gerald), Kim, S.-K. (Seung-Ki), Lee, J.Y. (Ji Yeoun), Rao, A.A.N. (Amulya A. Nageswara), Giannini, C. (Caterina), Li, K.K.W. (Kay Ka Wai), Ng, H.-K. (Ho-Keung), Yao, Y. (Yu), Kumabe, T. (Toshihiro), Tominaga, T. (Teiji), Grajkowska, W.A. (Wieslawa), Perek-Polnik, M. (Marta), Low, D.C.Y. (David C.Y.), Seow, W.T. (Wan Tew), Chang, K.T.E. (Kenneth T.E.), Mora, J. (Jaume), Pollack, A. (Aaron), Hamilton, R.L. (Ronald L.), Leary, S. (Sarah), Moore, A.S. (Andrew S.), Ingram, W.J. (Wendy J.), Hallahan, A.R. (Andrew R.), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Vasiljevic, A. (Alexandre), Faure-Conter, C. (Cecile), Shofuda, T. (Tomoko), Kagawa, N. (Naoki), Hashimoto, N. (Naoya), Jabado, N. (Nada), Weil, A.G. (Alexander G.), Gayden, T. (Tenzin), Wataya, T. (Takafumi), Shalaby, T. (Tarek), Grotzer, M. (Michael), Zitterbart, K. (Karel), Sterba, J., Kren, L. (Leos), Hortobágyi, T. (Tibor), Klekner, A. (Almos), Bognár, L. (László), Pócza, T. (Tímea), Hauser, P. (Peter), Schüller, U. (Ulrich), Jung, S. (Shin), Jang, W.-Y. (Woo-Youl), French, P.J. (Pim), Kros, J.M. (Johan), Veelen-Vincent, M.L.C. (Marie-Lise) van, Massimi, L. (Luca), Leonard, J.R. (Jeffrey), Rubin, J.B. (Joshua), Vibhakar, R. (Rajeev), Chambless, L.B. (Lola B.), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Faria, R. (Rui), Carvalho, A. (Alice), Nunes, S. (Sofia), Pimentel, J., Fan, X. (Xing), Muraszko, K.M. (Karin), López-Aguilar, E. (Enrique), Lyden, D. (David), Garzia, L. (Livia), Shih, D.J.H. (David J.), Kijima, N. (Noriyuki), Schneider, C. (Christian), Adamski, J. (Jennifer), Northcott, P.A. (Paul A.), Kool, M. (Marcel), Jones, D. (David), Chan, J.A. (Jennifer A.), Nikolic, A. (Ana), Garre, M.L. (Maria Luisa), Van Meir, E.G. (Erwin G.), Osuka, S. (Satoru), Olson, J.J. (Jeffrey J.), Jahangiri, A. (Arman), Castro, B.A. (Brandyn A.), Gupta, N. (Nalin), Weiss, W.A. (William A.), Moxon-Emre, I. (Iska), Mabbott, D.J. (Donald J.), Lassaletta, A. (Alvaro), Hawkins, C.E. (Cynthia), Tabori, U. (Uri), Drake, J. (James), Kulkarni, A. (Abhaya), Dirks, M. (Maaike), Rutka, J.T. (James), Korshunov, A. (Andrey), Pfister, S.M. (Stefan), Packer, R.J. (Roger J.), Ramaswamy, E.A., and Taylor, M.D. (Michael)
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 cm2 tumour remaining), or sub-total resection (≥1·5 cm2 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. 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 mod
Published: 2016
Full Text: View/download PDF

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

Author: Torchia, J, Golbourn, B, Feng, S, Ho, KC, Sin-Chan, P, Vasiljevic, A, Norman, JD, Guilhamon, P, Garzia, L, Agamez, NR, Lu, M, Chan, TS, Picard, D, de Antonellis, P, Khuong-Quang, D-A, Planello, AC, Zeller, C, Barsyte-Lovejoy, D, Lafay-Cousin, L, Letourneau, L, Bourgey, M, Yu, M, Gendoo, DMA, Dzamba, M, Barszczyk, M, Medina, T, Riemenschneider, AN, Morrissy, AS, Ra, Y-S, Ramaswamy, V, Remke, M, Dunham, CP, Yip, S, Ng, H-K, Lu, J-Q, Mehta, V, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Faria, CC, Roque, L, Fouladi, M, Hoffman, LM, Moore, AS, Wang, Y, Choi, SA, Hansford, JR, Catchpoole, D, Birks, DK, Foreman, NK, Strother, D, Klekner, A, Bognár, L, Garami, M, Hauser, P, Hortobágyi, T, Wilson, B, Hukin, J, Carret, A-S, Van Meter, TE, Hwang, EI, Gajjar, A, Chiou, S-H, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheinemann, K, Fleming, AJ, Johnston, DL, Michaud, J, Zelcer, S, Hammond, R, Afzal, S, Ramsay, DA, Sirachainan, N, Hongeng, S, Larbcharoensub, N, Grundy, RG, Lulla, RR, Fangusaro, JR, Druker, H, Bartels, U, Grant, R, Malkin, D, McGlade, CJ, Nicolaides, T, Tihan, T, Phillips, J, Majewski, J, Montpetit, A, Bourque, G, Bader, GD, Reddy, AT, Gillespie, GY, Warmuth-Metz, M, Rutkowski, S, Tabori, U, Lupien, M, Brudno, M, Schüller, U, Pietsch, T, Judkins, AR, Hawkins, CE, Bouffet, E, Kim, S-K, Dirks, PB, Taylor, MD, Erdreich-Epstein, A, Arrowsmith, CH, De Carvalho, DD, Rutka, JT, Jabado, N, Huang, A, Torchia, J, Golbourn, B, Feng, S, Ho, KC, Sin-Chan, P, Vasiljevic, A, Norman, JD, Guilhamon, P, Garzia, L, Agamez, NR, Lu, M, Chan, TS, Picard, D, de Antonellis, P, Khuong-Quang, D-A, Planello, AC, Zeller, C, Barsyte-Lovejoy, D, Lafay-Cousin, L, Letourneau, L, Bourgey, M, Yu, M, Gendoo, DMA, Dzamba, M, Barszczyk, M, Medina, T, Riemenschneider, AN, Morrissy, AS, Ra, Y-S, Ramaswamy, V, Remke, M, Dunham, CP, Yip, S, Ng, H-K, Lu, J-Q, Mehta, V, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Faria, CC, Roque, L, Fouladi, M, Hoffman, LM, Moore, AS, Wang, Y, Choi, SA, Hansford, JR, Catchpoole, D, Birks, DK, Foreman, NK, Strother, D, Klekner, A, Bognár, L, Garami, M, Hauser, P, Hortobágyi, T, Wilson, B, Hukin, J, Carret, A-S, Van Meter, TE, Hwang, EI, Gajjar, A, Chiou, S-H, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheinemann, K, Fleming, AJ, Johnston, DL, Michaud, J, Zelcer, S, Hammond, R, Afzal, S, Ramsay, DA, Sirachainan, N, Hongeng, S, Larbcharoensub, N, Grundy, RG, Lulla, RR, Fangusaro, JR, Druker, H, Bartels, U, Grant, R, Malkin, D, McGlade, CJ, Nicolaides, T, Tihan, T, Phillips, J, Majewski, J, Montpetit, A, Bourque, G, Bader, GD, Reddy, AT, Gillespie, GY, Warmuth-Metz, M, Rutkowski, S, Tabori, U, Lupien, M, Brudno, M, Schüller, U, Pietsch, T, Judkins, AR, Hawkins, CE, Bouffet, E, Kim, S-K, Dirks, PB, Taylor, MD, Erdreich-Epstein, A, Arrowsmith, CH, De Carvalho, DD, Rutka, JT, Jabado, N, and Huang, A
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. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

Author: Torchia, J, Golbourn, B, Feng, S, Ho, KC, Sin-Chan, P, Vasiljevic, A, Norman, JD, Guilhamon, P, Garzia, L, Agamez, NR, Lu, M, Chan, TS, Picard, D, de Antonellis, P, Khuong-Quang, D-A, Planello, AC, Zeller, C, Barsyte-Lovejoy, D, Lafay-Cousin, L, Letourneau, L, Bourgey, M, Yu, M, Gendoo, DMA, Dzamba, M, Barszczyk, M, Medina, T, Riemenschneider, AN, Morrissy, AS, Ra, Y-S, Ramaswamy, V, Remke, M, Dunham, CP, Yip, S, Ng, H-K, Lu, J-Q, Mehta, V, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Faria, CC, Roque, L, Fouladi, M, Hoffman, LM, Moore, AS, Wang, Y, Choi, SA, Hansford, JR, Catchpoole, D, Birks, DK, Foreman, NK, Strother, D, Klekner, A, Bognár, L, Garami, M, Hauser, P, Hortobágyi, T, Wilson, B, Hukin, J, Carret, A-S, Van Meter, TE, Hwang, EI, Gajjar, A, Chiou, S-H, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheinemann, K, Fleming, AJ, Johnston, DL, Michaud, J, Zelcer, S, Hammond, R, Afzal, S, Ramsay, DA, Sirachainan, N, Hongeng, S, Larbcharoensub, N, Grundy, RG, Lulla, RR, Fangusaro, JR, Druker, H, Bartels, U, Grant, R, Malkin, D, McGlade, CJ, Nicolaides, T, Tihan, T, Phillips, J, Majewski, J, Montpetit, A, Bourque, G, Bader, GD, Reddy, AT, Gillespie, GY, Warmuth-Metz, M, Rutkowski, S, Tabori, U, Lupien, M, Brudno, M, Schüller, U, Pietsch, T, Judkins, AR, Hawkins, CE, Bouffet, E, Kim, S-K, Dirks, PB, Taylor, MD, Erdreich-Epstein, A, Arrowsmith, CH, De Carvalho, DD, Rutka, JT, Jabado, N, Huang, A, Torchia, J, Golbourn, B, Feng, S, Ho, KC, Sin-Chan, P, Vasiljevic, A, Norman, JD, Guilhamon, P, Garzia, L, Agamez, NR, Lu, M, Chan, TS, Picard, D, de Antonellis, P, Khuong-Quang, D-A, Planello, AC, Zeller, C, Barsyte-Lovejoy, D, Lafay-Cousin, L, Letourneau, L, Bourgey, M, Yu, M, Gendoo, DMA, Dzamba, M, Barszczyk, M, Medina, T, Riemenschneider, AN, Morrissy, AS, Ra, Y-S, Ramaswamy, V, Remke, M, Dunham, CP, Yip, S, Ng, H-K, Lu, J-Q, Mehta, V, Albrecht, S, Pimentel, J, Chan, JA, Somers, GR, Faria, CC, Roque, L, Fouladi, M, Hoffman, LM, Moore, AS, Wang, Y, Choi, SA, Hansford, JR, Catchpoole, D, Birks, DK, Foreman, NK, Strother, D, Klekner, A, Bognár, L, Garami, M, Hauser, P, Hortobágyi, T, Wilson, B, Hukin, J, Carret, A-S, Van Meter, TE, Hwang, EI, Gajjar, A, Chiou, S-H, Nakamura, H, Toledano, H, Fried, I, Fults, D, Wataya, T, Fryer, C, Eisenstat, DD, Scheinemann, K, Fleming, AJ, Johnston, DL, Michaud, J, Zelcer, S, Hammond, R, Afzal, S, Ramsay, DA, Sirachainan, N, Hongeng, S, Larbcharoensub, N, Grundy, RG, Lulla, RR, Fangusaro, JR, Druker, H, Bartels, U, Grant, R, Malkin, D, McGlade, CJ, Nicolaides, T, Tihan, T, Phillips, J, Majewski, J, Montpetit, A, Bourque, G, Bader, GD, Reddy, AT, Gillespie, GY, Warmuth-Metz, M, Rutkowski, S, Tabori, U, Lupien, M, Brudno, M, Schüller, U, Pietsch, T, Judkins, AR, Hawkins, CE, Bouffet, E, Kim, S-K, Dirks, PB, Taylor, MD, Erdreich-Epstein, A, Arrowsmith, CH, De Carvalho, DD, Rutka, JT, Jabado, N, and Huang, A
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

19. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Author: Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, Jabado, N, Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, and Jabado, N
Abstract: Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.
Published: 2015

20. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

Author: Zhukova, N, Ramaswamy, V, Remke, M, Martin, DC, Castelo-Branco, P, Zhang, CH, Fraser, M, Tse, K, Poon, R, Shih, DJH, Baskin, B, Ray, PN, Bouffet, E, Dirks, P, von Bueren, AO, Pfaff, E, Korshunov, A, Jones, DTW, Northcott, PA, Kool, M, Pugh, TJ, Pomeroy, SL, Cho, YJ, Pietsch, T, Gessi, M, Rutkowski, S, Bognár, L, Cho, BK, Eberhart, CG, Conter, CF, Fouladi, M, French, PJ, Grajkowska, WA, Gupta, N, Hauser, P, Jabado, N, Vasiljevic, A, Jung, S, Kim, SK, Klekner, A, Kumabe, T, Lach, B, Leonard, JR, Liau, LM, Massimi, L, Pollack, IF, Ra, YS, Rubin, JB, Van Meir, EG, Wang, KC, Weiss, WA, Zitterbart, K, Bristow, RG, Alman, B, Hawkins, CE, Malkin, D, Clifford, SC, Pfister, SM, Taylor, MD, Tabori, U, Zhukova, N, Ramaswamy, V, Remke, M, Martin, DC, Castelo-Branco, P, Zhang, CH, Fraser, M, Tse, K, Poon, R, Shih, DJH, Baskin, B, Ray, PN, Bouffet, E, Dirks, P, von Bueren, AO, Pfaff, E, Korshunov, A, Jones, DTW, Northcott, PA, Kool, M, Pugh, TJ, Pomeroy, SL, Cho, YJ, Pietsch, T, Gessi, M, Rutkowski, S, Bognár, L, Cho, BK, Eberhart, CG, Conter, CF, Fouladi, M, French, PJ, Grajkowska, WA, Gupta, N, Hauser, P, Jabado, N, Vasiljevic, A, Jung, S, Kim, SK, Klekner, A, Kumabe, T, Lach, B, Leonard, JR, Liau, LM, Massimi, L, Pollack, IF, Ra, YS, Rubin, JB, Van Meir, EG, Wang, KC, Weiss, WA, Zitterbart, K, Bristow, RG, Alman, B, Hawkins, CE, Malkin, D, Clifford, SC, Pfister, SM, Taylor, MD, and Tabori, U
Published: 2014

21. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

Author: Dunn S., Cain J., Brennan C., Souweidane M.M., Jones C., Allis C.D., Brudno M., Becher O., Buczkowicz P., Hoeman C., Rakopoulos P., Pajovic S., Letourneau L., Dzamba M., Morrison A., Lewis P., Bouffet E., Bartels U., Zuccaro J., Agnihotri S., Ryall S., Barszczyk M., Chornenkyy Y., Bourgey M., Bourque G., Montpetit A., Cordero F., Castelo-Branco P., Mangerel J., Tabori U., Ho K.C., Huang A., Taylor K.R., Mackay A., Bendel A.E., Nazarian J., Fangusaro J.R., Karajannis M.A., Zagzag D., Foreman N.K., Donson A., Hegert J.V., Smith A., Chan J., Lafay-Cousin L., Hawkins C., Hukin J., Dunham C., Scheinemann K., Michaud J., Zelcer S., Ramsay D., Dunn S., Cain J., Brennan C., Souweidane M.M., Jones C., Allis C.D., Brudno M., Becher O., Buczkowicz P., Hoeman C., Rakopoulos P., Pajovic S., Letourneau L., Dzamba M., Morrison A., Lewis P., Bouffet E., Bartels U., Zuccaro J., Agnihotri S., Ryall S., Barszczyk M., Chornenkyy Y., Bourgey M., Bourque G., Montpetit A., Cordero F., Castelo-Branco P., Mangerel J., Tabori U., Ho K.C., Huang A., Taylor K.R., Mackay A., Bendel A.E., Nazarian J., Fangusaro J.R., Karajannis M.A., Zagzag D., Foreman N.K., Donson A., Hegert J.V., Smith A., Chan J., Lafay-Cousin L., Hawkins C., Hukin J., Dunham C., Scheinemann K., Michaud J., Zelcer S., and Ramsay D.
Abstract: Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. © 2014 Nature America, Inc. All rights reserved.
Published: 2014

22. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

Author: Dunn S., Cain J., Brennan C., Souweidane M.M., Jones C., Allis C.D., Brudno M., Becher O., Buczkowicz P., Hoeman C., Rakopoulos P., Pajovic S., Letourneau L., Dzamba M., Morrison A., Lewis P., Bouffet E., Bartels U., Zuccaro J., Agnihotri S., Ryall S., Barszczyk M., Chornenkyy Y., Bourgey M., Bourque G., Montpetit A., Cordero F., Castelo-Branco P., Mangerel J., Tabori U., Ho K.C., Huang A., Taylor K.R., Mackay A., Bendel A.E., Nazarian J., Fangusaro J.R., Karajannis M.A., Zagzag D., Foreman N.K., Donson A., Hegert J.V., Smith A., Chan J., Lafay-Cousin L., Hawkins C., Hukin J., Dunham C., Scheinemann K., Michaud J., Zelcer S., Ramsay D., Dunn S., Cain J., Brennan C., Souweidane M.M., Jones C., Allis C.D., Brudno M., Becher O., Buczkowicz P., Hoeman C., Rakopoulos P., Pajovic S., Letourneau L., Dzamba M., Morrison A., Lewis P., Bouffet E., Bartels U., Zuccaro J., Agnihotri S., Ryall S., Barszczyk M., Chornenkyy Y., Bourgey M., Bourque G., Montpetit A., Cordero F., Castelo-Branco P., Mangerel J., Tabori U., Ho K.C., Huang A., Taylor K.R., Mackay A., Bendel A.E., Nazarian J., Fangusaro J.R., Karajannis M.A., Zagzag D., Foreman N.K., Donson A., Hegert J.V., Smith A., Chan J., Lafay-Cousin L., Hawkins C., Hukin J., Dunham C., Scheinemann K., Michaud J., Zelcer S., and Ramsay D.
Abstract: Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. © 2014 Nature America, Inc. All rights reserved.
Published: 2014

23. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Author: Mack, S, Mack, S, Witt, H, Piro, R, Gu, L, Zuyderduyn, S, Stütz, A, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, D, Sill, M, Pugh, T, Ryzhova, M, Wani, K, Shih, D, Head, R, Remke, M, Bailey, S, Zichner, T, Faria, C, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, A, Northcott, P, Peacock, J, Bertrand, K, Agnihotri, S, Cavalli, F, Clarke, I, Nethery-Brokx, K, Creasy, C, Verma, S, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, M, Roberts, S, Fults, D, Massimi, L, Cho, Y, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, A, von Deimling, A, Witt, O, Scherer, S, Fan, X, Muraszko, K, Kool, M, Pomeroy, S, Jabado, N, Rutka, J, Bouffet, E, Korbel, J, Lupien, M, Aldape, K, Bader, G, Eils, R, Lichter, P, Dirks, P, Pfister, S, Korshunov, A, Taylor, M, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, P, Gupta, Nalin, Phillips, Joanna, Weiss, William, Mack, S, Mack, S, Witt, H, Piro, R, Gu, L, Zuyderduyn, S, Stütz, A, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, D, Sill, M, Pugh, T, Ryzhova, M, Wani, K, Shih, D, Head, R, Remke, M, Bailey, S, Zichner, T, Faria, C, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, A, Northcott, P, Peacock, J, Bertrand, K, Agnihotri, S, Cavalli, F, Clarke, I, Nethery-Brokx, K, Creasy, C, Verma, S, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, M, Roberts, S, Fults, D, Massimi, L, Cho, Y, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, A, von Deimling, A, Witt, O, Scherer, S, Fan, X, Muraszko, K, Kool, M, Pomeroy, S, Jabado, N, Rutka, J, Bouffet, E, Korbel, J, Lupien, M, Aldape, K, Bader, G, Eils, R, Lichter, P, Dirks, P, Pfister, S, Korshunov, A, Taylor, M, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, P, Gupta, Nalin, Phillips, Joanna, and Weiss, William
Abstract: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
Published: 2014

24. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Author: Mack, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stütz, A. M., Wang, X., Gallo, M., Garzia, L., Zayne, K., Zhang, X., Ramaswamy, V., Jäger, N., Jones, D. T. W., Sill, M., Pugh, T. J., Ryzhova, M., Wani, K. M., Shih, D. J. H., Head, R., Remke, M., Bailey, S. D., Zichner, T., Faria, C. C., Barszczyk, M., Stark, S., Seker-Cin, H., Hutter, S., Johann, P., Bender, S., Hovestadt, V., Tzaridis, T., Dubuc, A. M., Northcott, P. A., Peacock, J., Bertrand, K. C., Agnihotri, S., Cavalli, F. M. G., Clarke, I., Nethery-Brokx, K., Creasy, C. L., Verma, S. K., Koster, J., Wu, X., Yao, Y., Milde, T., Sin-Chan, P., Zuccaro, J., Lau, L., Pereira, S., Castelo-Branco, P., Hirst, M., Marra, M. A., Roberts, S. S., Fults, D., Massimi, Luca, Cho, Y. J., Van Meter, T., Grajkowska, W., Lach, B., Kulozik, A. E., Von Deimling, A., Witt, O., Scherer, S. W., Fan, X., Muraszko, K. M., Kool, M., Pomeroy, S. L., Gupta, N., Phillips, J., Huang, A., Tabori, U., Hawkins, C., Malkin, D., Kongkham, P. N., Weiss, W. A., Jabado, N., Rutka, J. T., Bouffet, E., Korbel, J. O., Lupien, M., Aldape, K. D., Bader, G. D., Eils, R., Lichter, P., Dirks, P. B., Pfister, S. M., Korshunov, A., Taylor, M. D., Massimi, L., Mack, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stütz, A. M., Wang, X., Gallo, M., Garzia, L., Zayne, K., Zhang, X., Ramaswamy, V., Jäger, N., Jones, D. T. W., Sill, M., Pugh, T. J., Ryzhova, M., Wani, K. M., Shih, D. J. H., Head, R., Remke, M., Bailey, S. D., Zichner, T., Faria, C. C., Barszczyk, M., Stark, S., Seker-Cin, H., Hutter, S., Johann, P., Bender, S., Hovestadt, V., Tzaridis, T., Dubuc, A. M., Northcott, P. A., Peacock, J., Bertrand, K. C., Agnihotri, S., Cavalli, F. M. G., Clarke, I., Nethery-Brokx, K., Creasy, C. L., Verma, S. K., Koster, J., Wu, X., Yao, Y., Milde, T., Sin-Chan, P., Zuccaro, J., Lau, L., Pereira, S., Castelo-Branco, P., Hirst, M., Marra, M. A., Roberts, S. S., Fults, D., Massimi, Luca, Cho, Y. J., Van Meter, T., Grajkowska, W., Lach, B., Kulozik, A. E., Von Deimling, A., Witt, O., Scherer, S. W., Fan, X., Muraszko, K. M., Kool, M., Pomeroy, S. L., Gupta, N., Phillips, J., Huang, A., Tabori, U., Hawkins, C., Malkin, D., Kongkham, P. N., Weiss, W. A., Jabado, N., Rutka, J. T., Bouffet, E., Korbel, J. O., Lupien, M., Aldape, K. D., Bader, G. D., Eils, R., Lichter, P., Dirks, P. B., Pfister, S. M., Korshunov, A., Taylor, M. D., and Massimi, L.
Abstract: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland. © 2014 Macmillan Publishers Limited.
Published: 2014

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

Author: Remke, M. (Marc), Ramaswamy, E.A., Peacock, M. (Munro), Shih, D.J.H. (David J.), Koelsche, C. (Christian), Northcott, P.A. (Paul A.), Hill, N. (Nadia), Cavalli, S. (Silvia), Kool, M. (Marcel), Wang, X. (Xin), Mack, S. (Stephen), Barszczyk, M. (Mark), Morrissy, A.S. (A. Sorana), Wu, X. (Xiaochong), Agnihotri, S. (Sameer), Luu, P. (Phan), Jones, D. (David), Garzia, L. (Livia), Dubuc, A.M. (Adrian), Zhukova, N. (Nataliya), Vanner, R. (Robert), Kros, J.M. (Johan), French, P.J. (Pim), Meir, E.G. (Erwin) van, Vibhakar, R. (Rajeev), Zitterbart, K. (Karel), Chan, J.A. (Jennifer), Bognár, L. (László), Klekner, A. (Almos), Lach, B. (Boleslaw), Jung, S. (Shin), Saad, F. (Fred), Liau, L.M. (Linda), Albrecht, S. (Steffen), Zollo, M. (Maurizio), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Delattre, O. (Olivier), Bourdeaut, F. (Franck), Doz, F.F. (François), Garami, M. (Miklós), Hauser, P. (Peter), Carlotti, C.G. (Carlos), Van Meter, T.E. (Timothy), Massimi, L. (Luca), Fults, D. (Daniel), Pomeroy, L.W. (Laura), Kumabe, T. (Toshiro), Ra, Y.S. (Young Shin), Leonard, J.R. (Jeffrey), Elbabaa, S.K. (Samer), Mora, J. (Jaume), Rubin, J.B. (Joshua), Cho, Y.-J. (Yoon-Jae), McLendon, R.E. (Roger), Bigner, D.D. (Darell), Eberhart, C.G. (Charles), Fouladi, M. (Maryam), Wechsler-Reya, R.J. (Robert), Faria, R. (Rui), Croul, S.E. (Sidney), Huang, A. (Anding), Bouffet, E. (Eric), Hawkins, C.E. (Cynthia), Dirks, M. (Maaike), Weiss, W.A. (William), Schüller, U. (Ulrich), Pollack, A. (Aaron), Rutkowski, P. (Piotr), Meyronet, D. (David), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Jabado, N. (Nada), Perek-Polnik, M. (Marta), Grajkowska, W.A. (Wieslawa), Kim, S.-K. (Seung-Ki), Rutka, J.T. (James), Malkin, E. (Elissa), Tabori, U. (Uri), Pfister, S.M. (Stefan), Korshunov, A. (Andrey), Deimling, A. (Andreas) von, Taylor, M.D. (Michael), Remke, M. (Marc), Ramaswamy, E.A., Peacock, M. (Munro), Shih, D.J.H. (David J.), Koelsche, C. (Christian), Northcott, P.A. (Paul A.), Hill, N. (Nadia), Cavalli, S. (Silvia), Kool, M. (Marcel), Wang, X. (Xin), Mack, S. (Stephen), Barszczyk, M. (Mark), Morrissy, A.S. (A. Sorana), Wu, X. (Xiaochong), Agnihotri, S. (Sameer), Luu, P. (Phan), Jones, D. (David), Garzia, L. (Livia), Dubuc, A.M. (Adrian), Zhukova, N. (Nataliya), Vanner, R. (Robert), Kros, J.M. (Johan), French, P.J. (Pim), Meir, E.G. (Erwin) van, Vibhakar, R. (Rajeev), Zitterbart, K. (Karel), Chan, J.A. (Jennifer), Bognár, L. (László), Klekner, A. (Almos), Lach, B. (Boleslaw), Jung, S. (Shin), Saad, F. (Fred), Liau, L.M. (Linda), Albrecht, S. (Steffen), Zollo, M. (Maurizio), Cooper, M.K. (Michael), Thompson, R.C. (Reid), Delattre, O. (Olivier), Bourdeaut, F. (Franck), Doz, F.F. (François), Garami, M. (Miklós), Hauser, P. (Peter), Carlotti, C.G. (Carlos), Van Meter, T.E. (Timothy), Massimi, L. (Luca), Fults, D. (Daniel), Pomeroy, L.W. (Laura), Kumabe, T. (Toshiro), Ra, Y.S. (Young Shin), Leonard, J.R. (Jeffrey), Elbabaa, S.K. (Samer), Mora, J. (Jaume), Rubin, J.B. (Joshua), Cho, Y.-J. (Yoon-Jae), McLendon, R.E. (Roger), Bigner, D.D. (Darell), Eberhart, C.G. (Charles), Fouladi, M. (Maryam), Wechsler-Reya, R.J. (Robert), Faria, R. (Rui), Croul, S.E. (Sidney), Huang, A. (Anding), Bouffet, E. (Eric), Hawkins, C.E. (Cynthia), Dirks, M. (Maaike), Weiss, W.A. (William), Schüller, U. (Ulrich), Pollack, A. (Aaron), Rutkowski, P. (Piotr), Meyronet, D. (David), Jouvet, A. (Anne), Fèvre-Montange, M. (Michelle), Jabado, N. (Nada), Perek-Polnik, M. (Marta), Grajkowska, W.A. (Wieslawa), Kim, S.-K. (Seung-Ki), Rutka, J.T. (James), Malkin, E. (Elissa), Tabori, U. (Uri), Pfister, S.M. (Stefan), Korshunov, A. (Andrey), Deimling, A. (Andreas) von, and Taylor, M.D. (Michael)
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
Published: 2013
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26. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Author: Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, Mirjam, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, XC, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, J.M., French, Pim, van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognar, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Albrecht, S, Liau, LM, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, Carlotti, CG, Van Meter, TE, Massimi, L, Fults, D, Pomeroy, SL, Kumabe, T, Ra, YS, Leonard, JR, Elbabaa, SK, Mora, J, Rubin, JB, Cho, YJ, McLendon, RE, Bigner, DD, Eberhart, CG, Fouladi, M, Wechsler-Reya, RJ, Faria, CC, Croul, SE, Huang, A, Bouffet, E, Hawkins, CE, Dirks, PB, Weiss, WA, Schuller, U, Pollack, IF, Rutkowski, S, Meyronet, D, Jouvet, A, Fevre-Montange, M, Jabado, N, Perek-Polnik, M, Grajkowska, WA, Kim, SK, Rutka, JT, Malkin, D, Tabori, U, Pfister, SM, Korshunov, A, von Deimling, A, Taylor, MD, Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, Mirjam, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, XC, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, J.M., French, Pim, van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognar, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Albrecht, S, Liau, LM, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, Carlotti, CG, Van Meter, TE, Massimi, L, Fults, D, Pomeroy, SL, Kumabe, T, Ra, YS, Leonard, JR, Elbabaa, SK, Mora, J, Rubin, JB, Cho, YJ, McLendon, RE, Bigner, DD, Eberhart, CG, Fouladi, M, Wechsler-Reya, RJ, Faria, CC, Croul, SE, Huang, A, Bouffet, E, Hawkins, CE, Dirks, PB, Weiss, WA, Schuller, U, Pollack, IF, Rutkowski, S, Meyronet, D, Jouvet, A, Fevre-Montange, M, Jabado, N, Perek-Polnik, M, Grajkowska, WA, Kim, SK, Rutka, JT, Malkin, D, Tabori, U, Pfister, SM, Korshunov, A, von Deimling, A, and Taylor, MD
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.
Published: 2013

27. CONTRIBUTION OF DNA COPY-NUMBER VARIATION (CNV) TO CANCER SUSCEPTIBILITY AND LARGE-SCALE GENOME ALTERATIONS IN OSTEOSARCOMA (OS)

Author: Pasic, I, Shlien, A, Novokmet, A, Zhang, C, Tabori, U, Pinto, D, Scherer, S W, Malkin, D, Pasic, I, Shlien, A, Novokmet, A, Zhang, C, Tabori, U, Pinto, D, Scherer, S W, and Malkin, D
Abstract: Introduction: OS, a common Li-Fraumeni syndrome (LFS)-associated neoplasm, is a common bone malignancy of children and adolescents. Sporadic OS is also characterized by young age of onset and high genomic instability, suggesting a genetic contribution to disease. This study examined the contribution of novel DNA structural variation elements, CNVs, to OS susceptibility. Given our finding of excessive constitutional DNA CNV in LFS patients, which often coincide with cancer-related genes, we hypothesized that constitutional CNV may also provide clues about the aetiology of LFS-related sporadic neoplasms like OS. Methods: CNV in blood DNA of 26 patients with sporadic OS was compared to that of 263 normal control samples from the International HapMap project, as well as 62 local controls. Analysis was performed on DNA hybridized to Affymetrix genome-wide human SNP array 6.0 by Partek Genomic Suite. Results: There was no detectable difference in average number of CNVs, CNV length, and total structural variation (product of average CNV number and length) between individuals with OS and controls. While this data is preliminary (small sample size), it argues against the presence of constitutional genomic instability in individuals with sporadic OS. Conclusion: We found that the majority of tumours from patients with sporadic OS show CN loss at chr3q13.31, raising the possibility that chr3q13.31 may represent a “driver” region in OS aetiology. In at least one OS tumour, which displays CN loss at chr3q13.31, we demonstrate decreased expression of a known tumour suppressor gene located at chr3q13.31. We are investigating the role ofchr3q13.31 in development of OS.
Published: 2008

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27 results on '"Tabori, U"'

1. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (cns) tumors and tropomyosin receptor kinase (trk) fusion.

2. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

3. HGG-11. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (CNS) tumors and tropomyosin receptor kinase (TRK) fusion.

4. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

5. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

6. Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

7. Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

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

9. HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS

10. NASPGHAN Annual Meeting Abstracts

11. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

12. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

13. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

14. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

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

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

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

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

19. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

20. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

21. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

22. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

23. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

24. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

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

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

27. CONTRIBUTION OF DNA COPY-NUMBER VARIATION (CNV) TO CANCER SUSCEPTIBILITY AND LARGE-SCALE GENOME ALTERATIONS IN OSTEOSARCOMA (OS)

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