Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and ...cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by
signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.
Karyotypic complexities associated with frequent loss or rearrangement of a number of chromosome arms, deletions, and mutations affecting the TP53 region, and molecular alterations of the INK4A gene ...have been reported in sporadic and/or neurofibromatosis type I (NF1)-related malignant peripheral nerve sheath tumors (MPNSTs). However, no investigations addressing possible different pathogenetic pathways in sporadic and NF1-associated MPNSTs have been reported. This lack is unexpected because, despite similar morphologic and immunophenotypic features, NF1-related cases are, by definition, associated with NF1 gene defects. Thus, we investigated the occurrence of TP53 and p16INK4A gene deregulation and the presence of microsatellite alterations at markers located at 17p, 17q, 9p21, 22q, 11q, 1p, or 2q loci in MPNSTs and neurofibromas either related (14 cases) or unrelated (14 cases) to NF1. Our results indicate that, in MPNSTs, p16INK4A inactivation almost equally affects both groups. However, TP53 mutations and loss of heterozygosity involving the TP53 locus (43% versus 9%), and p53 wild type overexpression, related or not to mdm2 overexpression (71% versus 25%), seem to mainly be restricted to sporadic MPNSTs. In NF1-associated MPNSTs, our microsatellite results are consistent with the occurrence of somatic inactivation by loss of heterozygosity of the second NF1 allele.
Neuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. Clinical distinction of stage 4s from lethal stage 4 can ...be difficult, but critical for therapeutic decisions. The aim of this study was to investigate chromosomal alterations and differential gene expression amongst infant disseminated NB subgroups.
Thirty-five NB tumours from patients diagnosed at < 18 months (25 stage 4 and 10 stage 4s), were evaluated by allelic and gene expression analyses.
All stage 4s patients underwent spontaneous remission, only 48% stage 4 patients survived despite combined modality therapy. Stage 4 tumours were 90% near-diploid/tetraploid, 44% MYCN amplified, 77% had 1p LOH (50% 1p36), 23% 11q and/or 14q LOH (27%) and 47% had 17q gain. Stage 4s were 90% near-triploid, none MYCN amplified and LOH was restricted to 11q. Initial comparison analyses between stage 4s and 4 < 12 months tumours revealed distinct gene expression profiles. A significant portion of genes mapped to chromosome 1 (P < 0.0001), 90% with higher expression in stage 4s, and chromosome 11 (P = 0.0054), 91% with higher expression in stage 4. Less definite expression profiles were observed between stage 4s and 4 < 18m, yet, association with chromosomes 1 (P < 0.0001) and 11 (P = 0.005) was maintained. Distinct gene expression profiles but no significant association with specific chromosomal region localization was observed between stage 4s and stage 4 < 18 months without MYCN amplification.
Specific chromosomal aberrations are associated with distinct gene expression profiles which characterize spontaneously regressing or aggressive infant NB, providing the biological basis for the distinct clinical behaviour.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Hamartomas of mature cardiac myocytes (HMCM) are rare cardiac tumors typically developing in the ventricular wall, but they have also been reported involving the atria.•We describe a case of HMCM ...presenting as an epicardial mass with a polypoid configuration attached to the interatrial groove.•The diagnosis of HMCM is by histological examination.•Although HMCM are not associated with any known molecular or cytogenetic abnormalities, we identified fusions transcripts along with complex copy number anomalies of chromosome 7.
Hamartoma of mature cardiac myocytes (HMCM) is an extremely rare cardiac tumor characterized by benign growth of differentiated mature striated cardiac myocytes, and usually involves the ventricular myocardium. We describe the case of a 15-year-old female who presented with a short history of atrial fibrillation and a polypoid epicardial tumor that was attached to the interatrial groove by a short pedicle. The resected specimen showed features consistent with HMCM. Although these tumors are not associated with any known molecular or cytogenetic abnormalities, we identified fusions transcripts along with complex copy number anomalies of chromosome 7.
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade ...neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.
Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, ...whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.
Significance We present, to our knowledge, the first comprehensive next-generation sequencing of osteosarcoma in combination with a functional genomic screen in a genetically defined mouse model of osteosarcoma. Our data provide a strong rationale for targeting the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in osteosarcoma and a foundation for rational clinical trial design. These findings present an immediate clinical opportunity because multiple inhibitors of this pathway are currently in clinical trials.
A recent study showed glutamate receptor delta 2 antibodies (GluD2-ab) in sera of patients with opsoclonus-myoclonus syndrome (OMS). Inconsistencies between cerebellar immunoreactivity and expression ...of GluD2 led us to hypothesize that these antibodies are not biomarkers of OMS.
Serum of 45 children with OMS (10 22% with neuroblastoma), 158 adults with OMS (53 34% with tumors), and 172 controls including 134 patients with several types of neurologic disorders, 18 with neuroblastoma without OMS, and 20 healthy participants were investigated. Antibodies were determined with 3 different techniques: (1) rat brain immunohistochemistry, (2) a live cell-based assay using a standard secondary antibody (2-step CBA), and (3) a similar CBA with a secondary and tertiary antibodies (3-step CBA). Two plasmids were used in the CBA studies. Three commercial GluD2-ab and 2 human sera with GluD2-ab served as controls for expression of GluD2.
The 3 commercial GluD2-ab showed predominant reactivity with the molecular and Purkinje cell layers (where GluD2 is highly enriched), and were also positive with the indicated CBAs. Substantially milder reactivity with brain tissue and CBA was obtained with the 2 control human sera containing GluD2-ab. None of the 203 patients with OMS and 172 controls showed immunoreactivities consistent with GluD2-abs. Compared with a standard 2-step CBA, the 3-step assay did not improve antibody detection and showed more frequent nonspecific reactivity that was not immunoabsorbed with GluD2.
We did not find GluD2-ab in a large cohort of patients with OMS. GluD2-ab should not be considered diagnostic biomarkers of OMS.
PIK3CA‐related congenital haemangioma Luque‐Luna, Mar; Ivars, Marta; Lavarino, Cinzia Emilia ...
Journal of the European Academy of Dermatology and Venereology,
July 2024, Letnik:
38, Številka:
7
Journal Article
Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic ...stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.
Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.
Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 chr11, chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.
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.
Abstract
Medulloblastoma (MB) is the most frequent malignant childhood brain tumor. Four molecular subgroups have been described (WNT, SHH, group3, group4), which are associated with a different ...biological profile, prognosis, specific MRI characteristics and patterns of metastatic dissemination. We aimed to determine the imaging features of the metastatic MB and its molecular subgroup and their outcomes. Retrospective single-center analytic-observational study conducted from January 2004-January 2022 in a tertiary-care center. Pediatric patients with metastatic medulloblastoma at disease onset were included. We collected epidemiological and clinical characteristics, treatment received, and outcomes. The molecular subgroup was determined by its methylation profile. MRI were reviewed by the neuroradiologist. Sixty-three patients were diagnosed, 17 (26.9%) were metastatic. The median age at diagnosis was 5.1 years (range 2.1-17.5 years), 58.8% were male. According to histopathologic classification, fifteen patients (93.8%) were classic,1 (6.3%) desmoplastic. Molecular subgroup analysis showed 2 WNT (12.5%), 1 SHH (6.3%), 3 (18.8%) group 3 (G3) and 5 (31.2%) group 4 (G4). Four patients (25%) were classified as G3/G4 and 1 (6.3%) as mixed. Five patients (29.4%) were M2 and 12 patients (70.6%) were M3 according to Chang staging system. The location in the cerebellar hemispheres was only observed in SHH patient while G3 tumors presented homogeneous contrast enhancement. All WNT, G3 and G4 were located in IV ventricle. We found no association between molecular subgroup and metastatic site (intracranial vs spinal, Fisher test, p=0.45). All patients presented with metastasis in the third ventricular infundibular recess were G4. Four patients died, all of them were G3 or G3/G4. Our results supported the literature previously reported. According to the MRI imaging features, the molecular medulloblastoma subgroups could be suggested. The presence of metastasis in the infundibular recess suggested MB group 4. However, the dissemination pattern could not be associated with any subgroup in our series.
PDF
