Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based ...on its lack of reproducibility in predicting patients’ outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
Display omitted
•DNA methylation profiling of ependymomas identifies nine molecular subgroups•YAP1 and RELA fusions characterize two distinct groups of supratentorial ependymoma•Patients with PFA or supratentorial RELA-positive ependymoma show dismal prognosis•Risk stratification by molecular subgrouping is superior to histological grading
Pajtler et al. classify 500 ependymal tumors using DNA methylation profiling into nine molecular subgroups. This molecular classification outperforms the current histopathological grading in the risk stratification of patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the ...(epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.
Display omitted
•Highly divergent posttranscriptional pathway regulation in MB subgroups•Phosphoproteomic profiles reveal specific kinase activity in MB subgroups•Identification of aberrant ERBB4-SRC signaling as a hallmark of group 4 MBs•Over expression of activated SRC in the developing cerebellum induces MB
Using proteomic analyses, Forget et al. unravel divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas (MB) and identify aberrant ERBB4-SRC signaling in group 4. Expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 MB.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive ...malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently ...associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients. Combinatory molecular analyses reveal that Chd7 is required for the maintenance of open chromatin and thus activation of genes essential for granule neuron differentiation. We further demonstrate that both Chd7 and Top2b are necessary for the transcription of a set of long neuronal genes in cerebellar granule neurons. Altogether, our comprehensive analyses reveal a mechanism with chromatin remodellers governing brain development via controlling a core transcriptional programme for cell-specific differentiation.
Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased ...proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor
are recurrent and enriched in SHH medulloblastoma. To investigate
as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of
(
) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCOR
). While
alone did not promote tumorigenesis or affect GNP differentiation,
combined with loss of the SHH receptor gene
resulted in fully penetrant medulloblastomas. In
;
tumors, the growth factor gene
was aberrantly up-regulated, and ectopic
overexpression was sufficient to drive tumorigenesis in
GNPs. BCOR directly regulates
, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the
promoter in
;
tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to
overexpression, which transforms preneoplastic cells to malignant tumors.
Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, ...suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
Display omitted
•ATRTs are comprised of three epigenetically distinct subgroups: TYR, SHH, and MYC•H3K27Ac enhancer landscapes reveal ATRT subgroup-specific regulatory networks•Regulatory networks lead to identification of potential therapeutic targets•Epigenetic profiles point at distinct cellular origins of ATRT subgroups
SMARCB1 is the sole highly recurrently mutated gene in atypical teratoid/rhabdoid tumors (ATRTs). Johann et al. show that ATRTs are composed of three epigenetic subgroups that have different clinical characteristics, and identify subgroup-specific regulatory networks that suggest potential therapeutic targets.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary ...resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
Display omitted
•SHH-MBs in infants, children, and adults are genomically distinct from each other•Most adult, but only half of the pediatric, SHH-MBs will respond to SMO inhibition•Tumor predisposition (PTCH1, SUFU, TP53) is highly prevalent in pediatric SHH-MB•Recurrent mutations outside the SHH-pathway suggest rational combination therapies
Smoothened (SMO) inhibitors are in clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB), but response varies. By profiling a large SHH-MB cohort, Kool et al. reveal age-dependent genomic distinction and demonstrate genotype-related response to SMO inhibition using patient-derived xenograft cells.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with ...divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.
Full text
Available for:
IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Introduction
Closed incision negative‐pressure therapy (CINPT) has been shown to shorten the time to heal in post‐bariatric abdominoplasty and to lower seroma rates in cosmetic abdominoplasty. The ...objective of this study was to assess the effect of CINPT on donor‐site morbidity following abdominal‐based free‐flap breast reconstruction.
Patients and Methods
We reviewed medical records from 225 women who had undergone 300 microsurgical free‐flap breast reconstructions from the abdomen from November 1, 2007 to March 31, 2019. Patients were grouped according to wound therapy, including 127 patients in the standard of care group and 98 patients in the CINPT group. Primary outcomes were minor (non‐operative) and major (operative) surgical site complications. Secondary outcomes were time to drain removal, in‐hospital length, and scar quality.
Results
Analysis of patient demographics showed an equal distribution with regard to the age, smoking status, prevalence of diabetes mellitus, preoperative chemotherapy, and previous abdominal surgery in both groups. Significantly more patients with obesity (29.6 vs. 15.8%; p = .01) and bilateral breast reconstruction (40.8 vs. 27.6%; p = .04) were included in the CINPT group. Compared to standard of care, the CINPT group had a lower incidence of major surgical site complications (26.0 vs. 11.2%; p = .001). There was no difference in minor surgical site complications and secondary outcomes between groups.
Conclusion
The CINPT represents a reliable tool to reduce surgical site complications on the abdominal donor‐site in abdominal‐based free‐flap breast reconstruction.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Brain tumors are the most frequent category of solid tumors in children and have the highest mortality rate among all pediatric cancers. Although diagnosis and treatment have improved ...prognosis over the past decades for some childhood brain tumors, others remain lethal and current treatments are highly toxic to the developing brain, resulting in severe sequelae and considerably affecting the patient’s quality of life. Thus, new therapeutic options with reduced secondary effects are urgently needed. From this perspective, immunotherapies have gained a lot of attention due to their effectiveness in targeting tumor cells specifically. Chimeric-antigen receptor (CAR) T-cells recognize the target antigen on the surface of. CD276 is an immune checkpoint molecule that is expressed in a variety of solid tumor entities, including pediatric brain tumors. We analyzed the CD276 expression in our Patient-Derived-Xenograft (PDX) biobank of brain tumors and found that CD276 is ubiquitously expressed (ATRT, MB, EPN, GBM, ETMR, etc). Flow cytometry of MB PDX (n=4) confirmed CD276 expression of 97-99% of tumor cells, indicating that CD276 might be a good antigen target for CAR-T cell therapy of MBG3 and MBSHH. We found that second generation CAR-T cells targeting CD276 antigen significantly decreased tumor burden of the most aggressive MB subgroups (G3 and SHH-TP53mut PDX models) in NSG mice. We further treated NSG mice carrying a high tumor burden of the aggressive SHH-TP53mut PDX BT084 with second (CD28) and third generation (CD28-41BB) CD276-CAR-T cells. While both 2nd and 3rd generation improved the survival rates compared with CD19-CAR-T control cells, we found no difference in survival between the CD276 CAR-T generations, with no severe secondary effect during treatment. In conclusion, CD276 is a good antigen target for medulloblastoma, and warrants further evaluation for the treatment of medulloblastoma patients at relapse or as a maintenance therapy after standard treatment.
PDF
