Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

Johann, Pascal; Erkek, Serap; Zapatka, Marc; Kerl, Kornelius; Buchhalter, Ivo; Hovestadt, Volker; Jones, David; Sturm, Dominik; Hermann, Carl; Segura-Wang, Maia; Korshunov, Andrey; Rhyzova, Marina; Gröbner, Susanne; Brabetz, Sebastian; Chávez, Lukas; Bens, Susanne; Gröschel, Stefan; Kratochwil, Fabian; Wittmann, Andrea; Sieber, Laura; Geörg, Christina; Wolf, Steffen; Beck, Katja; Oyen, Florian; Capper, David; Sluis, Peter van; Volckmann, Richard; Koster, Jan; Versteeg, Rogier; Deimling, Andreas von; Milde, Till; Witt, Olaf; Kulozik, Andreas E.; Ebinger, Martin; Shalaby, Tarek; Grotzer, Michael A.; Sumerauer, David; Zámečnı́k, Josef; Mora, Jaume; Jabado, Nada; Taylor, Michael D.; Huang, Annie; Aronica, Eleonora; Bertoni, Anna; Radlwimmer, Bernhard; Pietsch, Torsten; Schüller, Ulrich; Schneppenheim, Reinhard; Northcott, Paul A.; Korbel, Jan; Siebert, Reiner; Frühwald, Michael C.; Lichter, Peter; Eils, Roland; Gajjar, Amar; Hasselblatt, Martin; Pfister, Stefan M.; Kool, Marcel

doi:10.1016/j.ccell.2016.02.001

Cited by 450 publications

(552 citation statements)

References 34 publications

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“…2d). Notably, all ATRTs with signature P1 were in the recently defined subgroup 'SHH' , and even within one proposed methylation subset of these 17 (P = 0.003, Wilcoxon rank-sum test; Extended Data Fig. 2d).…”

Section: Mutational Processes In Childhood Cancersmentioning

confidence: 94%

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

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1,108

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The landscape of genomic alterations across childhood cancers a list of authors and affiliations appears at the end of the paper. OPENPan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.Cure rates for childhood cancers have increased to about 80% in recent decades, but cancer is still the leading cause of death by disease in the developed world among children over one year of age 1,2 . Furthermore, many children who survive cancer suffer from long-term sequelae of surgery, cytotoxic chemotherapy, and radiotherapy, including mental disabilities, organ toxicities, and secondary cancers 3 . A crucial step in developing more specific and less damaging therapies is the unravelling of the complete genetic repertoire of paediatric malignancies, which differ from adult malignancies in terms of their histopathological entities and molecular subtypes 4 . Over the past few years, many entityspecific sequencing efforts have been launched, but the few paediatric pan-cancer studies thus far have focused only on mutation frequencies, germline predisposition, and alterations in epigenetic regulators [4][5][6] .We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA) 7 . We have also examined mutational signatures and potential drug targets. The compendium of genetic alterations presented here is available to the scientific community at http://www.pedpancan.com.This integrative analysis includes 24 types of cancer and covers all major childhood cancer entities, many of which occur exclusively in children 8 (Fig. 1, Supplementary Table 1). Ninety-five per cent of the patients in this study were diagnosed during childhood or adolescence (aged 18 years or younger) and 5% as young adults (up to 25 years) (Extended Data ...

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Section: Mutational Processes In Childhood Cancersmentioning

confidence: 94%

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

Self Cite

1,108

1,156

View full text Add to dashboard Cite

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“…Subgroup specific transcription factor regulatory networks were constructed as previously described with only few amendments 8,25 . H3K27ac data of the samples within the same subgroup were combined.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Mack¹,

Pajtler

Chávez

et al. 2017

Nature

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SUMMARY Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated based on anatomical location – supratentorial region (ST) or posterior fossa (PF) – and further divided into distinct molecular subgroups that reflect differences in age of onset, gender predominance, and response to therapy1–3. The most common and aggressive subgroup, Posterior Fossa Ependymoma Group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, Posterior Fossa Ependymoma Group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses yet favourable clinical outcomes1,3. Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1).1,3,4 Subependymomas, a distinct histologic variant, can also be found within the ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively1. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts with the goal of identifying essential super enhancer associated genes on which tumour cells were dependent. Enhancer regions revealed putative oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, diminished proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

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“…The ongoing and detailed characterization of AT/RT and MRT (50,51) will likely lead to further biological insights that can better delineate molecular subtypes of these tumors and may lead to novel therapeutic avenues. Despite this progress, how best to approach early cancer surveillance for germline carriers at risk for these rare and aggressive tumors is likely to remain an area of significant clinical challenge.…”

Section: Discussionmentioning

confidence: 99%

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

Foulkes

Kamihara

Evans

et al. 2017

Clinical Cancer Research

147

113

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Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU). SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive “rhabdoid” term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations. Clin Cancer Res; 23(12); e62–e67. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

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Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

Cited by 450 publications

References 34 publications

The landscape of genomic alterations across childhood cancers

The landscape of genomic alterations across childhood cancers

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

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