BCOR‐ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central ...nervous system BCOR‐ITD (CNS BCOR‐ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high‐grade endometrial stromal sarcoma, and in the bone and soft tissue as undifferentiated round cell sarcoma or primitive myxoid mesenchymal tumour of infancy. Based on a series of 33 retrospective cases, including 10 CNS BCOR‐ITD and 23 BCOR‐ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological, and histopathological findings, and molecular signatures. Whole‐transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. BCOR‐ITD tumours mostly affected young children with a median age at diagnosis of 2.1 years (range 0–62.4). Median overall survival was 3.9 years and progression‐free survival was 1.4 years. This dismal prognosis is shared among tumours in all locations except CCSK. Histopathological review revealed marked differences between CNS BCOR‐ITD and BCOR‐ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n = 22) and DNA methylation (n = 21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single‐cell RNA‐Seq atlases suggests that the distinction between BCOR‐ITD sarcomas and CNS BCOR‐ITD may result from differences in cells of origin.
DNA copy number profiles characterize regions of chromosome gains, losses and breakpoints in tumor genomes. Although many models have been proposed to detect these alterations, it is not clear which ...model is appropriate before visual inspection the signal, noise and models for a particular profile.
We propose SegAnnDB, a Web-based computer vision system for genomic segmentation: first, visually inspect the profiles and manually annotate altered regions, then SegAnnDB determines the precise alteration locations using a mathematical model of the data and annotations. SegAnnDB facilitates collaboration between biologists and bioinformaticians, and uses the University of California, Santa Cruz genome browser to visualize copy number alterations alongside known genes.
The breakpoints project on INRIA GForge hosts the source code, an Amazon Machine Image can be launched and a demonstration Web site is http://bioviz.rocq.inria.fr.
Germline predisposing pathogenic variants (GPVs) are present in approximately 8–10 % of children with all cancer types. Very rare tumours (VRTs) represent many different diseases, defined with an ...annual incidence < 2 / 1,000,000, and correspond to 11 % of all cancers in patients aged 0–14 years. Some of these VRTs, including cancer typical for adults, develop in children with a cancer predisposition syndrome (CPS). Classically, three situations lead to consider this association: Some patients develop a VRT for which histology itself strongly suggests a GPV related to a CPS; others are referred for germline genetic testing because of a family or personal history and finally, a systematic molecular genomic tumour analysis, reveals a PV typical to a CPS. Depending on the samples tested and type of analysis performed, information can be directly available about the germline status of such a PV. Depicting the association between CPS and VRT is clinically important as some of these tumour types require adapted therapy, sometimes in the frontline setting, and the proposal of a specific surveillance programme to detect other malignancies. The diagnosis of CPS necessitates a careful familial evaluation and genetic counselling regarding the risks faced by the child or other family members. The aim of this paper is to propose a literature review of solid VRTs occurring in paediatric and young adult patients associated with CPSs.
•Very rare tumours correspond to 11 % of all paediatric cancers.•Some are (strongly) associated with a cancer predisposition syndrome.•In some cases, cancer treatment must be adapted to avoid severe toxicities.•Screening programmes serve to depict these tumours early, inform families and improve outcome.
In that respect, because chromothripsis medulloblastoma indicates the presence of TP53 mutations and can subsequently induce familial screening,4 finding insights for HRD and BRCA2 and PALB2 ...mutations in a child with medulloblastoma might eventually cause the initiation of tumour screening in the relatives. Since early cancer detection in unaffected individuals is one major goal of genetic counselling, possible familial consequences of broad genetic analyses on tumour DNA will need to be explicitly anticipated with parents; moreover, the medical benefit and psychological effects of such findings on families with no cancer history should be prospectively evaluated. ...the study does not identify any specific predisposing genes for group 3 and group 4 medulloblastomas, which shows that a young age at cancer onset (group 3) might not indicate a strong probability of predisposing syndrome per se. Alternatively, this outcome might also indicate that the predisposing genes for these groups lie outside the list of cancer genes that was assessed here. ...although many studies have investigated this class of high-penetrance predisposition genes, the contribution of low-penetrance, high-frequency alleles remains unknown and still needs to be investigated through genome-wide association studies for medulloblastoma.
Somatic alterations in the tumor suppressor gene SMARCB1 were first described in the malignant rhabdoid tumor (MRT) of infancy. Since then, SMARCB1 alterations have been found in other tumors, ...forming a varied group of SMARCB1- deficient tumors, which sometimes shares overlapping immunohistochemical and histological findings. Thus, the diagnosis is challenging. We report two cases of pediatric SMARCB1 -deficient tumors from the clivus that illustrate the diagnostic difficulties. Both cases were strongly positive for epithelial markers associated with loss of BAF47 (INI1) expression, and were negative for S100 and CD34. Molecular analyses of the SMARCB1 gene found a deletion of all nine exons in both cases. In the first case, a 5-year-old girl presented with a thoracic metastasis of a clival tumor, which was diagnosed as MRT and treated accordingly. The morphological findings and the expression of brachyury would favor the diagnosis of a poorly differentiated chordoma. The second case was a quickly fatal clival tumor in a 2-year-old boy: This tumor was morphologically undifferentiated and raises the problem of differential diagnosis between an MRT, a malignant myoepithelial tumor, or an undifferentiated chordoma due to the location and the expression of brachyury. Studies of biological signatures, such as transcriptome profiling, could help to understand the apparent overlap between these tumors.
CNS tumors, isolated from a series of primitive neuroectodermal tumors by a distinct methylation profile, were initially named high-grade neuroepithelial tumors (HGNET) with BCOR alteration 4. ...Because almost all HGNET-BCOR harbored BCOR ITD and of an unknown cellular origin, the cIMPACT-NOW update 6 recommends the terminology “CNS tumor with BCOR ITD” 4,5,6. ...DNA methylation clustering showed a close proximity of these cases to sarcomas with BCOR alterations. Because DNA methylation profiles are thought to represent a combination of both somatically acquired DNA methylation changes and a signature reflecting the cell of origin, and because no extra-CNS lesion was found in our cases, it is therefore reasonable to believe that they represent another tumor type than classical CNS tumors with BCOR ITD. Teramura Y, Tanaka M, Yamazaki Y, Yamashita K, Takazawa Y, Ae K et al (2020) Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model.
Hereditary predisposition to neuroblastoma accounts for less than 5% of neuroblastomas and is probably heterogeneous. Recently, a predisposition gene has been mapped to 16p12-p13, but has not yet ...been identified. Occurrence of neuroblastoma in association with congenital central hypoventilation and Hirschsprung's disease suggests that genes, involved in the development of neural-crest-derived cells, may be altered in these conditions. The recent identification of
PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma. We report a family with three first-degree relatives with neuroblastic tumours (namely two ganglioneuromas and one neuroblastoma) in one branch and two siblings with Hirschsprung's disease in another branch. A constitutional R100L
PHOX2B mutation was identified in all three patients affected with tumours. We also report a germline
PHOX2B mutation in one patient treated for Hirschsprung's disease who subsequently developed a multifocal neuroblastoma in infancy. Both mutations disrupt the homeodomain of the
PHOX2B protein. No loss of heterozygosity at the
PHOX2B locus was observed in the tumour, suggesting that haplo-insufficiency, gain of function or dominant negative effects may account for the oncogenic effects of these mutations. These observations identify
PHOX2B as the first predisposing gene to hereditary neuroblastic tumours.
Abstract
Background
Atypical teratoid/rhabdoid tumors (ATRTs) are known to exhibit molecular and clinical heterogeneity even though SMARCB1 inactivation is the sole recurrent genetic event present in ...nearly all cases. Indeed, recent studies demonstrated 3 molecular subgroups of ATRTs that are genetically, epigenetically, and clinically distinct. As these studies included different numbers of tumors, various subgrouping techniques, and naming, an international working group sought to align previous findings and to reach a consensus on nomenclature and clinicopathological significance of ATRT subgroups.
Methods
We integrated various methods to perform a meta-analysis on published and unpublished DNA methylation and gene expression datasets of ATRTs and associated clinicopathological data.
Results
In concordance with previous studies, the analyses identified 3 main molecular subgroups of ATRTs, for which a consensus was reached to name them ATRT-TYR, ATRT-SHH, and ATRT-MYC. The ATRT-SHH subgroup exhibited further heterogeneity, segregating further into 2 subtypes associated with a predominant supratentorial (ATRT-SHH-1) or infratentorial (ATRT-SHH-2) location. For each ATRT subgroup we provide an overview of its main molecular and clinical characteristics, including SMARCB1 alterations and pathway activation.
Conclusions
The introduction of a common classification, characterization, and nomenclature of ATRT subgroups will facilitate future research and serve as a common ground for subgrouping patient samples and ATRT models, which will aid in refining subgroup-based therapies for ATRT patients.
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