Baudis, Michael

Bidinotto, Lucas

Bjerke, Lynn

Burford, Anna

Hmida, Dorra

Ingram, Wendy

Jones, Chris

Mackay, Alan

Marshall, Lynley

Molinari, Valeria

Moore, Andrew

Mu, Kun

Nandhabalan, Meera

Ng, H.K.

Popov, Sergey

Reis, Rui

Taylor, Katy

Trabelsi, Saoussen

Vinci, Mara

von Bueren, Andre

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N E U RO - O N CO LO G YAbstractsHG-11. INTEGRATIVE MOLECULAR META-ANALYSIS OF 700PEDIATRIC HIGH GRADE GLIOMA AND DIPG DEFINESWIDESPREAD INTER- AND INTRA-TUMORALHETEROGENEITYAlan Mackay1, Mara Vinci1, Anna Burford1, Lynn Bjerke1, Katy Taylor1,Meera Nandhabalan1, Lynley Marshall1, Valeria Molinari1, Sergey Popov1,Wendy Ingram2, AndrewMoore2, Saoussen Trabelsi3, Dorra Hmida3,KunMu4, Lucas Bidinotto5, Rui Reis5, H.K. Ng6, Andre von Bueren7,Michael Baudis8, and Chris Jones1; 1Institute of Cancer Research, London,UK; 2Queensland Childrens Medical research Institute, Brisbane, Australia;3CHU Farhat HACHED, Sousse, Tunisia; 4Qilu Hospital, Jinan, China;5Barretos Cancer Hospital, Barretos, Brazil; 6Chinese University of HongKong, Hong Kong, Hong Kong; 7University of Goettingen, Goettingen,Germany; 8University of Zurich, Zurich, SwitzerlandRecent molecular profiling studies of paediatric high grade (pHGG) anddiffuse intrinsic pontine glioma (DIPG) have refined these tumours intoage- and location-based subgroups driven by unique genetic and epigenetic al-terations, however individual studies are underpowered to investigatesubgroup-specific events. We have retrieved publicly available genome-widedata from560 pHGG/DIPG samples and combined this with140 unpub-lished cases including young adults up to the age of 30 years.Wehave integrat-ed multiple array-based and sequencing platforms to produce DNA copynumber profiles from 700 tumours, 500 with clinicopathological andhistone H3 annotation, and .300 of which have full somatic sequence infor-mation.We identified subgroup-specific genetic alterations co-segregating, ormutually exclusive, with known driving histonemutations. H3.3G34R/V ce-rebral hemispheric tumours harbour significantly more CNAs and SNVs thanother subgroups. These included novel amplified loci at 1p13.3 (KCNA) and ahistone cluster at 6p22.2, though lacked key amplified loci such as MYC/MYCN. H3.1K27M DIPG were distinct from H3.3K27M primarily on thebasis of whole arm chromosomal changes (enriched +2, -16q; reduced -17panda lackofTP53mutations).H3.3K27Mtumoursharboured specifically en-riched known (7q31.2;MET) and novel amplicons (17p11.2;TOP3A).Integration with mutation data identified subgroup-independent, non-overlapping pathway-level recurrent alterations, such as RTK-PI3K-mTOR,dysregulated in 55% cases and conferring shorter survival in hemispheric,but not other locations. Aswell as inter-tumoral differences, deeper interroga-tion of the sequencing data also reveals substantial intra-tumoral heterogene-ity.Whilst driving histoneH3mutations were found to be present in 100% ofcells, mutations in genes such as PDGFRA and PIK3CA were predominantlyfound at subclonal levels, and tumours from all locations were inferred to becomprised ofmultiple subclonal populations,withH3.3G34R/V themost ge-netically diverse. These data improve our understanding of the underlyingbiology of pHGG/DIPG, and will provide rational targets for subgroup-specific and –independent therapies.Neuro-Oncology 17:iii1–iii40, 2015.doi:10.1093/neuonc/nov061.48#The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rightsreserved. For permissions, please e-mail: journals.permissions@oup.com.

HG-11INTEGRATIVE MOLECULAR META-ANALYSIS OF 700 PEDIATRIC HIGH GRADE GLIOMA AND DIPG DEFINES WIDESPREAD INTER- AND INTRA-TUMORAL HETEROGENEITY

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HG-11INTEGRATIVE MOLECULAR META-ANALYSIS OF 700 PEDIATRIC HIGH GRADE GLIOMA AND DIPG DEFINES WIDESPREAD INTER- AND INTRA-TUMORAL HETEROGENEITY

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