eprintid: 1558227 rev_number: 32 eprint_status: archive userid: 608 dir: disk0/01/55/82/27 datestamp: 2017-06-01 13:05:21 lastmod: 2021-12-06 00:43:37 status_changed: 2017-07-17 15:14:01 type: article metadata_visibility: show creators_name: Schwalbe, EC creators_name: Lindsey, JC creators_name: Nakjang, S creators_name: Crosier, S creators_name: Smith, AJ creators_name: Hicks, D creators_name: Rafiee, G creators_name: Hill, RM creators_name: Iliasova, A creators_name: Stone, T creators_name: Pizer, B creators_name: Michalski, A creators_name: Joshi, A creators_name: Wharton, SB creators_name: Jacques, TS creators_name: Bailey, S creators_name: Williamson, D creators_name: Clifford, SC title: Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study ispublished: pub divisions: UCL divisions: B02 divisions: D13 divisions: G22 keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, BETA-CATENIN STATUS, CURRENT CONSENSUS, GENETIC PROFILES, TUMOR, INHIBITION, EXPRESSION, MUTATIONS, PATHWAY, GENOME note: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ abstract: Background International consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. Methods In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children’s Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0–16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3–16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Findings Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into agedependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant; n=65) and childhood patients (≥4·3 years; MBSHH-Child; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR [n=65] and MBGrp4-HR [n=85]) and low-risk (MBGrp3-LR [n=50] and MBGrp4-LR [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroupdependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82–100]); standard risk (50 [23%] patients; 81% survival [70–94]); highrisk (82 [38%] patients; 42% survival [31–56]); and very high-risk (29 [13%] patients; 28% survival [14–56]). Interpretation The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. date: 2017-05-22 date_type: published publisher: ELSEVIER SCIENCE INC official_url: http://doi.org/10.1016/S1470-2045(17)30243-7 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1296612 doi: 10.1016/S1470-2045(17)30243-7 lyricists_name: Jacques, Thomas lyricists_name: Stone, Thomas lyricists_id: TJACQ32 lyricists_id: STONE38 actors_name: Jacques, Thomas actors_name: Stacey, Thomas actors_id: TJACQ32 actors_id: TSSTA20 actors_role: owner actors_role: impersonator full_text_status: public publication: Lancet Oncology volume: 18 number: 7 pagerange: 958-971 pages: 14 issn: 1474-5488 citation: Schwalbe, EC; Lindsey, JC; Nakjang, S; Crosier, S; Smith, AJ; Hicks, D; Rafiee, G; ... Clifford, SC; + view all <#> Schwalbe, EC; Lindsey, JC; Nakjang, S; Crosier, S; Smith, AJ; Hicks, D; Rafiee, G; Hill, RM; Iliasova, A; Stone, T; Pizer, B; Michalski, A; Joshi, A; Wharton, SB; Jacques, TS; Bailey, S; Williamson, D; Clifford, SC; - view fewer <#> (2017) Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncology , 18 (7) pp. 958-971. 10.1016/S1470-2045(17)30243-7 <https://doi.org/10.1016/S1470-2045%2817%2930243-7>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1558227/1/Jacques-T_novel%20molecular_classification_child_.pdf