MBCL-44. THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (iMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)

Abstract BACKGROUND iMB has inferior survival to older children principally due to radiation-sparing therapy. To better understand which patients may benefit from radiation-sparing protocols, we describe the molecular landscape of iMB and report the iMB outcome on the SJYC07 trial designed to defer,...

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Veröffentlicht in:	Neuro-oncology (Charlottesville, Va.) Va.), 2018-06, Vol.20 (suppl_2), p.i126-i127
Hauptverfasser:	Robinson, Giles W, Rudneva, Vasilisa A, Buchhalter, Ivo, Billups, Catherine A, Waszak, Sebastian M, Smith, Kyle, Bowers, Daniel C, Bendel, Anne, Fisher, Paul, Partap, Sonia, Crawford, John, Hassall, Tim, Indelicato, Daniel J, Boop, Frederick, Klimo, Paul, Sabin, Noah D, Patay, Zoltan, Merchant, Thomas E, Stewart, Clinton F, Orr, Brent A, Korbel, Jan O, Jones, David T W, Sharma, Tanvi, Lichter, Peter, Kool, Marcel, Korshunov, Andrey, Pfister, Stefan M, Gilbertson, Richard J, Sanders, Robert P, Onar-Thomas, Arzu, Ellison, David W, Gajjar, Amar, Northcott, Paul A
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creator	Robinson, Giles W Rudneva, Vasilisa A Buchhalter, Ivo Billups, Catherine A Waszak, Sebastian M Smith, Kyle Bowers, Daniel C Bendel, Anne Fisher, Paul Partap, Sonia Crawford, John Hassall, Tim Indelicato, Daniel J Boop, Frederick Klimo, Paul Sabin, Noah D Patay, Zoltan Merchant, Thomas E Stewart, Clinton F Orr, Brent A Korbel, Jan O Jones, David T W Sharma, Tanvi Lichter, Peter Kool, Marcel Korshunov, Andrey Pfister, Stefan M Gilbertson, Richard J Sanders, Robert P Onar-Thomas, Arzu Ellison, David W Gajjar, Amar Northcott, Paul A
description	Abstract BACKGROUND iMB has inferior survival to older children principally due to radiation-sparing therapy. To better understand which patients may benefit from radiation-sparing protocols, we describe the molecular landscape of iMB and report the iMB outcome on the SJYC07 trial designed to defer, reduce, or delay radiation exposure. METHODS We assembled a molecular cohort of 190 iMBs and a SJYC07 trial cohort of 81 iMBs. Tumors were sub-classified into molecular subgroups based on DNA methylation profiles and overlaid with mutations and copy-number alterations. PFS and OS for the SJYC07 cohort was estimated across clinical risk groups, consensus molecular subgroups, and in the context of novel MB subtypes. RESULTS Computational analysis of DNA methylation array data divided iMB into three of the four consensus subgroups: SHH, G3, and G4 (absent WNT). Clinical outcome of iMBSHH was superior to iMBGroup3/Group4 (5-year PFS: 51 ± 8% vs 11 ± 10%, P
doi_str_mv	10.1093/neuonc/noy059.440
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THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (iMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Robinson, Giles W ; Rudneva, Vasilisa A ; Buchhalter, Ivo ; Billups, Catherine A ; Waszak, Sebastian M ; Smith, Kyle ; Bowers, Daniel C ; Bendel, Anne ; Fisher, Paul ; Partap, Sonia ; Crawford, John ; Hassall, Tim ; Indelicato, Daniel J ; Boop, Frederick ; Klimo, Paul ; Sabin, Noah D ; Patay, Zoltan ; Merchant, Thomas E ; Stewart, Clinton F ; Orr, Brent A ; Korbel, Jan O ; Jones, David T W ; Sharma, Tanvi ; Lichter, Peter ; Kool, Marcel ; Korshunov, Andrey ; Pfister, Stefan M ; Gilbertson, Richard J ; Sanders, Robert P ; Onar-Thomas, Arzu ; Ellison, David W ; Gajjar, Amar ; Northcott, Paul A</creator><creatorcontrib>Robinson, Giles W ; Rudneva, Vasilisa A ; Buchhalter, Ivo ; Billups, Catherine A ; Waszak, Sebastian M ; Smith, Kyle ; Bowers, Daniel C ; Bendel, Anne ; Fisher, Paul ; Partap, Sonia ; Crawford, John ; Hassall, Tim ; Indelicato, Daniel J ; Boop, Frederick ; Klimo, Paul ; Sabin, Noah D ; Patay, Zoltan ; Merchant, Thomas E ; Stewart, Clinton F ; Orr, Brent A ; Korbel, Jan O ; Jones, David T W ; Sharma, Tanvi ; Lichter, Peter ; Kool, Marcel ; Korshunov, Andrey ; Pfister, Stefan M ; Gilbertson, Richard J ; Sanders, Robert P ; Onar-Thomas, Arzu ; Ellison, David W ; Gajjar, Amar ; Northcott, Paul A</creatorcontrib><description>Abstract BACKGROUND iMB has inferior survival to older children principally due to radiation-sparing therapy. To better understand which patients may benefit from radiation-sparing protocols, we describe the molecular landscape of iMB and report the iMB outcome on the SJYC07 trial designed to defer, reduce, or delay radiation exposure. METHODS We assembled a molecular cohort of 190 iMBs and a SJYC07 trial cohort of 81 iMBs. Tumors were sub-classified into molecular subgroups based on DNA methylation profiles and overlaid with mutations and copy-number alterations. PFS and OS for the SJYC07 cohort was estimated across clinical risk groups, consensus molecular subgroups, and in the context of novel MB subtypes. RESULTS Computational analysis of DNA methylation array data divided iMB into three of the four consensus subgroups: SHH, G3, and G4 (absent WNT). Clinical outcome of iMBSHH was superior to iMBGroup3/Group4 (5-year PFS: 51 ± 8% vs 11 ± 10%, P<0.001; 5-year OS: 72 ± 8% vs 51 ± 12%, P<0.05). t-distributed stochastic neighbor embedding (t-SNE) analysis recognized two subtypes of iMBSHH (iMBSHH-I and iMBSHH-II) and distributed iMBGroup3/Group4 into eight recently described subtypes (I-VIII). 5-year PFS of iMBSHH-II surpassed iMBSHH-I (75 ± 10% vs 28 ± 10%, P=0.003) and exceeded 90% in low-risk iMBSHH-II (<3y, M0, R0, DN/MBEN). CONCLUSION Through integrative genomics, we described the molecular landscape of iMB. Application of these data to a trial cohort identifies: a low-risk SHH-subtype (iMBSHH-II) that exhibits excellent PFS in the absence of radiation, intra-ventricular chemotherapy, and high-dose chemotherapy; a high-risk SHH-subtype (iMBSHH-I); and very poor PFS for iMBGroup3/Group4. These findings will shape risk stratification on future iMB trials.</description><identifier>ISSN: 1522-8517</identifier><identifier>EISSN: 1523-5866</identifier><identifier>DOI: 10.1093/neuonc/noy059.440</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Abstracts</subject><ispartof>Neuro-oncology (Charlottesville, Va.), 2018-06, Vol.20 (suppl_2), p.i126-i127</ispartof><rights>The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012030/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012030/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1584,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Robinson, Giles W</creatorcontrib><creatorcontrib>Rudneva, Vasilisa A</creatorcontrib><creatorcontrib>Buchhalter, Ivo</creatorcontrib><creatorcontrib>Billups, Catherine A</creatorcontrib><creatorcontrib>Waszak, Sebastian M</creatorcontrib><creatorcontrib>Smith, Kyle</creatorcontrib><creatorcontrib>Bowers, Daniel C</creatorcontrib><creatorcontrib>Bendel, Anne</creatorcontrib><creatorcontrib>Fisher, Paul</creatorcontrib><creatorcontrib>Partap, Sonia</creatorcontrib><creatorcontrib>Crawford, John</creatorcontrib><creatorcontrib>Hassall, Tim</creatorcontrib><creatorcontrib>Indelicato, Daniel J</creatorcontrib><creatorcontrib>Boop, Frederick</creatorcontrib><creatorcontrib>Klimo, Paul</creatorcontrib><creatorcontrib>Sabin, Noah D</creatorcontrib><creatorcontrib>Patay, Zoltan</creatorcontrib><creatorcontrib>Merchant, Thomas E</creatorcontrib><creatorcontrib>Stewart, Clinton F</creatorcontrib><creatorcontrib>Orr, Brent A</creatorcontrib><creatorcontrib>Korbel, Jan O</creatorcontrib><creatorcontrib>Jones, David T W</creatorcontrib><creatorcontrib>Sharma, Tanvi</creatorcontrib><creatorcontrib>Lichter, Peter</creatorcontrib><creatorcontrib>Kool, Marcel</creatorcontrib><creatorcontrib>Korshunov, Andrey</creatorcontrib><creatorcontrib>Pfister, Stefan M</creatorcontrib><creatorcontrib>Gilbertson, Richard J</creatorcontrib><creatorcontrib>Sanders, Robert P</creatorcontrib><creatorcontrib>Onar-Thomas, Arzu</creatorcontrib><creatorcontrib>Ellison, David W</creatorcontrib><creatorcontrib>Gajjar, Amar</creatorcontrib><creatorcontrib>Northcott, Paul A</creatorcontrib><title>MBCL-44. THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (iMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)</title><title>Neuro-oncology (Charlottesville, Va.)</title><description>Abstract BACKGROUND iMB has inferior survival to older children principally due to radiation-sparing therapy. To better understand which patients may benefit from radiation-sparing protocols, we describe the molecular landscape of iMB and report the iMB outcome on the SJYC07 trial designed to defer, reduce, or delay radiation exposure. METHODS We assembled a molecular cohort of 190 iMBs and a SJYC07 trial cohort of 81 iMBs. Tumors were sub-classified into molecular subgroups based on DNA methylation profiles and overlaid with mutations and copy-number alterations. PFS and OS for the SJYC07 cohort was estimated across clinical risk groups, consensus molecular subgroups, and in the context of novel MB subtypes. RESULTS Computational analysis of DNA methylation array data divided iMB into three of the four consensus subgroups: SHH, G3, and G4 (absent WNT). Clinical outcome of iMBSHH was superior to iMBGroup3/Group4 (5-year PFS: 51 ± 8% vs 11 ± 10%, P<0.001; 5-year OS: 72 ± 8% vs 51 ± 12%, P<0.05). t-distributed stochastic neighbor embedding (t-SNE) analysis recognized two subtypes of iMBSHH (iMBSHH-I and iMBSHH-II) and distributed iMBGroup3/Group4 into eight recently described subtypes (I-VIII). 5-year PFS of iMBSHH-II surpassed iMBSHH-I (75 ± 10% vs 28 ± 10%, P=0.003) and exceeded 90% in low-risk iMBSHH-II (<3y, M0, R0, DN/MBEN). CONCLUSION Through integrative genomics, we described the molecular landscape of iMB. Application of these data to a trial cohort identifies: a low-risk SHH-subtype (iMBSHH-II) that exhibits excellent PFS in the absence of radiation, intra-ventricular chemotherapy, and high-dose chemotherapy; a high-risk SHH-subtype (iMBSHH-I); and very poor PFS for iMBGroup3/Group4. These findings will shape risk stratification on future iMB trials.</description><subject>Abstracts</subject><issn>1522-8517</issn><issn>1523-5866</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqNkctO3DAUhqMKpHLpA3TnJUhk8CWJJ11U8hhPx8hJRnEGiZXlJA6dCpJRwlTigfqeDQQh2LE658j-vnOk3_O-IzhDMCaXrdt3bXXZdk8wjGdBAL94RyjExA_nUXTw0mN_HiL61Tsehj8QYhRG6Mj7lyy48oNgBoqVAEmmBN8olgOWXgGuZCo5U0CNk-ZsLUC2BDJdsrQAibjaKJUtFNNFljBwtk0W5z9ALvRGFfqFf29j6lZLDZZ5lgAG1nmm14IX8kZcgGQEJBdpIXKwXjEtgJSgyOW4-Exf33JIz0-9w8beD-7baz3xNktR8JWvsl_PF_oVohT6OGqwpdCGTegaMie2QZDWpMQNdBg7QknoYFzHMZ3XQUBJacsohhRVNXGlDWpy4v2cvLt9-eDqyrWPvb03u377YPsn09mt-fjSbn-bu-6viSDCkMBRgCZB1XfD0LvmjUXQPAdlpqDMFJQZgxqZi4np9rtPfP8PK8iMcg</recordid><startdate>20180622</startdate><enddate>20180622</enddate><creator>Robinson, Giles W</creator><creator>Rudneva, Vasilisa A</creator><creator>Buchhalter, Ivo</creator><creator>Billups, Catherine A</creator><creator>Waszak, Sebastian M</creator><creator>Smith, Kyle</creator><creator>Bowers, Daniel C</creator><creator>Bendel, Anne</creator><creator>Fisher, Paul</creator><creator>Partap, Sonia</creator><creator>Crawford, John</creator><creator>Hassall, Tim</creator><creator>Indelicato, Daniel J</creator><creator>Boop, Frederick</creator><creator>Klimo, Paul</creator><creator>Sabin, Noah D</creator><creator>Patay, Zoltan</creator><creator>Merchant, Thomas E</creator><creator>Stewart, Clinton F</creator><creator>Orr, Brent A</creator><creator>Korbel, Jan O</creator><creator>Jones, David T W</creator><creator>Sharma, Tanvi</creator><creator>Lichter, Peter</creator><creator>Kool, Marcel</creator><creator>Korshunov, Andrey</creator><creator>Pfister, Stefan M</creator><creator>Gilbertson, Richard J</creator><creator>Sanders, Robert P</creator><creator>Onar-Thomas, Arzu</creator><creator>Ellison, David W</creator><creator>Gajjar, Amar</creator><creator>Northcott, Paul A</creator><general>Oxford University Press</general><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20180622</creationdate><title>MBCL-44. THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (iMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)</title><author>Robinson, Giles W ; Rudneva, Vasilisa A ; Buchhalter, Ivo ; Billups, Catherine A ; Waszak, Sebastian M ; Smith, Kyle ; Bowers, Daniel C ; Bendel, Anne ; Fisher, Paul ; Partap, Sonia ; Crawford, John ; Hassall, Tim ; Indelicato, Daniel J ; Boop, Frederick ; Klimo, Paul ; Sabin, Noah D ; Patay, Zoltan ; Merchant, Thomas E ; Stewart, Clinton F ; Orr, Brent A ; Korbel, Jan O ; Jones, David T W ; Sharma, Tanvi ; Lichter, Peter ; Kool, Marcel ; Korshunov, Andrey ; Pfister, Stefan M ; Gilbertson, Richard J ; Sanders, Robert P ; Onar-Thomas, Arzu ; Ellison, David W ; Gajjar, Amar ; Northcott, Paul A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1770-26f2a70a5f5ef383af107d3b2f0e22e3735e09d9978d4473bab69071cd3eba4d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Abstracts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Robinson, Giles W</creatorcontrib><creatorcontrib>Rudneva, Vasilisa A</creatorcontrib><creatorcontrib>Buchhalter, Ivo</creatorcontrib><creatorcontrib>Billups, Catherine A</creatorcontrib><creatorcontrib>Waszak, Sebastian M</creatorcontrib><creatorcontrib>Smith, Kyle</creatorcontrib><creatorcontrib>Bowers, Daniel C</creatorcontrib><creatorcontrib>Bendel, Anne</creatorcontrib><creatorcontrib>Fisher, Paul</creatorcontrib><creatorcontrib>Partap, Sonia</creatorcontrib><creatorcontrib>Crawford, John</creatorcontrib><creatorcontrib>Hassall, Tim</creatorcontrib><creatorcontrib>Indelicato, Daniel J</creatorcontrib><creatorcontrib>Boop, Frederick</creatorcontrib><creatorcontrib>Klimo, Paul</creatorcontrib><creatorcontrib>Sabin, Noah D</creatorcontrib><creatorcontrib>Patay, Zoltan</creatorcontrib><creatorcontrib>Merchant, Thomas E</creatorcontrib><creatorcontrib>Stewart, Clinton F</creatorcontrib><creatorcontrib>Orr, Brent A</creatorcontrib><creatorcontrib>Korbel, Jan O</creatorcontrib><creatorcontrib>Jones, David T W</creatorcontrib><creatorcontrib>Sharma, Tanvi</creatorcontrib><creatorcontrib>Lichter, Peter</creatorcontrib><creatorcontrib>Kool, Marcel</creatorcontrib><creatorcontrib>Korshunov, Andrey</creatorcontrib><creatorcontrib>Pfister, Stefan M</creatorcontrib><creatorcontrib>Gilbertson, Richard J</creatorcontrib><creatorcontrib>Sanders, Robert P</creatorcontrib><creatorcontrib>Onar-Thomas, Arzu</creatorcontrib><creatorcontrib>Ellison, David W</creatorcontrib><creatorcontrib>Gajjar, Amar</creatorcontrib><creatorcontrib>Northcott, Paul A</creatorcontrib><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuro-oncology (Charlottesville, Va.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robinson, Giles W</au><au>Rudneva, Vasilisa A</au><au>Buchhalter, Ivo</au><au>Billups, Catherine A</au><au>Waszak, Sebastian M</au><au>Smith, Kyle</au><au>Bowers, Daniel C</au><au>Bendel, Anne</au><au>Fisher, Paul</au><au>Partap, Sonia</au><au>Crawford, John</au><au>Hassall, Tim</au><au>Indelicato, Daniel J</au><au>Boop, Frederick</au><au>Klimo, Paul</au><au>Sabin, Noah D</au><au>Patay, Zoltan</au><au>Merchant, Thomas E</au><au>Stewart, Clinton F</au><au>Orr, Brent A</au><au>Korbel, Jan O</au><au>Jones, David T W</au><au>Sharma, Tanvi</au><au>Lichter, Peter</au><au>Kool, Marcel</au><au>Korshunov, Andrey</au><au>Pfister, Stefan M</au><au>Gilbertson, Richard J</au><au>Sanders, Robert P</au><au>Onar-Thomas, Arzu</au><au>Ellison, David W</au><au>Gajjar, Amar</au><au>Northcott, Paul A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MBCL-44. THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (iMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)</atitle><jtitle>Neuro-oncology (Charlottesville, Va.)</jtitle><date>2018-06-22</date><risdate>2018</risdate><volume>20</volume><issue>suppl_2</issue><spage>i126</spage><epage>i127</epage><pages>i126-i127</pages><issn>1522-8517</issn><eissn>1523-5866</eissn><abstract>Abstract BACKGROUND iMB has inferior survival to older children principally due to radiation-sparing therapy. To better understand which patients may benefit from radiation-sparing protocols, we describe the molecular landscape of iMB and report the iMB outcome on the SJYC07 trial designed to defer, reduce, or delay radiation exposure. METHODS We assembled a molecular cohort of 190 iMBs and a SJYC07 trial cohort of 81 iMBs. Tumors were sub-classified into molecular subgroups based on DNA methylation profiles and overlaid with mutations and copy-number alterations. PFS and OS for the SJYC07 cohort was estimated across clinical risk groups, consensus molecular subgroups, and in the context of novel MB subtypes. RESULTS Computational analysis of DNA methylation array data divided iMB into three of the four consensus subgroups: SHH, G3, and G4 (absent WNT). Clinical outcome of iMBSHH was superior to iMBGroup3/Group4 (5-year PFS: 51 ± 8% vs 11 ± 10%, P<0.001; 5-year OS: 72 ± 8% vs 51 ± 12%, P<0.05). t-distributed stochastic neighbor embedding (t-SNE) analysis recognized two subtypes of iMBSHH (iMBSHH-I and iMBSHH-II) and distributed iMBGroup3/Group4 into eight recently described subtypes (I-VIII). 5-year PFS of iMBSHH-II surpassed iMBSHH-I (75 ± 10% vs 28 ± 10%, P=0.003) and exceeded 90% in low-risk iMBSHH-II (<3y, M0, R0, DN/MBEN). CONCLUSION Through integrative genomics, we described the molecular landscape of iMB. Application of these data to a trial cohort identifies: a low-risk SHH-subtype (iMBSHH-II) that exhibits excellent PFS in the absence of radiation, intra-ventricular chemotherapy, and high-dose chemotherapy; a high-risk SHH-subtype (iMBSHH-I); and very poor PFS for iMBGroup3/Group4. These findings will shape risk stratification on future iMB trials.</abstract><cop>US</cop><pub>Oxford University Press</pub><doi>10.1093/neuonc/noy059.440</doi><oa>free_for_read</oa></addata></record>
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title	MBCL-44. THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (iMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)
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