SUMMARY While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

A B S T R A C T PurposeReports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. Patients and MethodsWe determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. ResultsTP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P Ͻ .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P Ͻ .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; Ϯ SE) was 41% Ϯ 9% and 81% Ϯ 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P Ͻ .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% Ϯ 9% and 97% Ϯ 3% for patients with WNT tumors with and without TP53 mutations (P ϭ .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P ϭ .012) and not WNT tumors. ConclusionSubgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

SUMMARY 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.

SummaryBackgroundIncomplete surgical resection of medulloblastoma is controversially considered a marker of high-risk disease; driving aggressive surgical resections, “second-look” surgeries, and/or intensified chemoradiotherapy. All prior publications evaluating the clinical importance of extent of resection (EOR) failed to account for molecular subgroup. We analysed the prognostic value of EOR across 787 medulloblastoma samples in a subgroup-specific manner.MethodsWe retrospectively identified patients from Medulloblastoma Advanced Genomics International Consortium (MAGIC) centres with a histological diagnosis of medulloblastoma and complete extent of resection and survival data. Specimens were collected from 35 international institutions. Medulloblastoma subgroup affiliation was determined using nanoString gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. Extent of resection (EOR) based on post-operative imaging was classified as gross total (GTR), near total (NTR, <1·5cm2), or subtotal (STR, ≥ 1·5cm2). Overall survival (OS) and progression-free survival (PFS) multivariable analyses including subgroup, age, metastatic status, geographical location of therapy (North America/Australia vs world), and adjuvant therapy regimen were performed. The primary endpoint was the impact of surgical EOR by molecular subgroup and other clinical variables on OS and PFS.Findings787 medulloblastoma patients (86 WNT, 242 SHH, 163 Group 3, and 296 Group 4) were included in a multivariable Cox model of PFS and OS. The marked benefit of EOR in the overall cohort was greatly attenuated after including molecular subgroup in the multivariable analysis. There was an observed PFS benefit of GTR over STR (hazard ration [HR] 1·45, 95% CI; 1·07–1·96, p=0·02) but there was no observed PFS or OS benefit of GTR over NTR (HR 1·05, 0·71–1·53, p=0·82 and HR 1·14, 0·75–1·72, p=0.55). There was no statistically significant survival benefit to greater EOR for patients with WNT, SHH, or Group 3 patients (HR 1·03, 0·67–1·58, p=0·9 for STR vs. GTR). There was a PFS benefit for GTR over STR in patients with Group 4 medulloblastoma (HR1·97, 1·22–3·17, p=0·01), particularly those with metastatic disease (HR 2·22, 1–4·93, p=0·05). A nomogram based on this multivariable cox proportional hazards model shows the comparably smaller impact of EOR on relative risk for PFS and OS than subgroup affiliation, metastatic status, radiation dose, and adjuvant chemotherapy.InterpretationThe prognostic benefit of EOR for patients with medulloblastoma is attenuated after accounting for molecular subgroup affiliation. Although maximal safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high as there is no definitive benefit to GTR over NTR. Our results suggest a re-evaluation of the long-term implications of intensified craniospinal irradiation (36 Gy) in children with small residual portions of medullobla...

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Deregulation of the cyclin D‐CDK4/6‐INK4‐RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle‐specific mechanisms and cell cycle‐nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.