Publications by authors named "Benjamin Ellezam"

45 Publications

Histopathological features of systemic sclerosis-associated myopathy: A scoping review.

Autoimmun Rev 2021 May 7:102851. Epub 2021 May 7.

Division of Rheumatology, Centre hospitalier de l'Université de Montréal (CHUM), CHUM Research Center, Department of Medicine, Université de Montréal, Montréal, Québec, Canada. Electronic address:

Background: Scleromyositis (SM) is an emerging subset of myositis associated with features of systemic sclerosis (SSc) but it is currently not recognized as a distinct histopathological subset by the European NeuroMuscular Center (ENMC). Our aim was to review studies reporting muscle biopsies from SSc patients with myositis and to identify unique histopathological features of SM.

Methods: A scoping review was conducted and included all studies reporting histopathological findings in SSc patients with myositis searching the following databases: PubMed, MEDLINE, EMBASE, CINAHL and EBM-Reviews. Clinical, serological, and histopathological data were extracted using a standardized protocol.

Results: Out of 371 citations, 77 studies that included 559 muscle biopsies were extracted. Fifty-seven percent (n = 227/400) had inflammatory infiltrates, predominantly T cells, which were endomysial (49%), perimysial (42%) and perivascular (41%). Few studies (18%, n = 8/44) evaluated the presence of B-cells. Myofiber atrophy was present in 48% (n = 104/218) of biopsies, and was predominantly perifascicular in 19% (n = 6/31), with necrosis reported in 56% (n = 162/290) of cases. Sarcolemmal MHC-I upregulation was found in 72% (n = 64/89) of biopsies. Non-specified C5b-9 deposition was described in 39% of muscle biopsies (n = 28/72). Neurogenic features were present in 23% (n = 44/191); endomysial fibrosis was reported in 35% (n = 120/340); and rimmed vacuoles were observed in 32% (n = 11/34) of biopsies. Capillaropathy, such as capillary dropout and/or ultrastructural endothelial abnormalities, was reported in 33% (n = 43/129) of cases. Reported ENMC categories were mainly polymyositis (21%), non-specific myositis (19%), immune-mediated necrotizing myopathy (16%), and dermatomyositis (8%). Histopathological features were analyzed according to serological subtypes in 28 studies, including anti-PM-Scl (n = 48), -Ku (n = 23) and -U1RNP (n = 90). Most of these biopsies demonstrated inflammatory infiltrates (range 49-85%) as well as MHC-I expression (range 63-81%). Necrosis was associated with anti-Ku (85%) and anti-U1RNP (73%), while anti-Ku was also associated with neurogenic features and rimmed vacuoles in 57% and 25% of cases, respectively.

Conclusion: Our review suggests that SM is characterized by heterogeneous pathological features using definitions included in current histopathological criteria. Whether a distinct histopathological signature exists in SM remains to be determined. SSc-specific and SSc-associated autoantibodies may help define more homogeneous histopathological subsets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2021.102851DOI Listing
May 2021

Statin-associated anti-HMGCR immune-mediated necrotizing myopathy with dermatomyositis-like features: A case report.

SAGE Open Med Case Rep 2020 29;8:2050313X20984120. Epub 2020 Dec 29.

Division of Rheumatology, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy is a subtype of idiopathic inflammatory myopathy which may be associated with statin exposure. It presents with severe proximal muscle weakness, high creatine kinase levels and muscle fiber necrosis. Treatment with intravenous immunoglobulins and immunosuppressants is often necessary. This entity is not commonly known among dermatologists as there are usually no extramuscular manifestations. We report a rare case of statin-associated anti-HMGCR immune-mediated necrotizing myopathy with dermatomyositis-like cutaneous features. The possibility of anti-HMGCR immune-mediated necrotizing myopathy should be considered in patients with cutaneous dermatomyositis-like features associated with severe proximal muscle weakness, highly elevated creatine kinase levels and possible statin exposure. This indicates the importance of muscle biopsy and specific autoantibody testing for accurate diagnosis, as well as significant therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2050313X20984120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780312PMC
December 2020

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients.

Curr Oncol 2021 Jan 9;28(1):346-366. Epub 2021 Jan 9.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.

Neurotrophic tyrosine receptor kinase gene fusions () are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., infantile fibrosarcoma [IFS]) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/curroncol28010038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903261PMC
January 2021

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Cell 2020 12 30;183(6):1617-1633.e22. Epub 2020 Nov 30.

Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791404PMC
December 2020

Multisystem Proteinopathy Associated with a G156S Mutation in a French Canadian Family.

Can J Neurol Sci 2020 05;47(3):412-415

Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2020.25DOI Listing
May 2020

Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians.

Ann Neurol 2020 04 8;87(4):568-583. Epub 2020 Feb 8.

Department of Child Neurology, Centre Hospitalier de l'Université Laval et Centre Mère-Enfant Soleil, Université Laval, Quebec City, Quebec, Canada.

Objective: Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy.

Methods: Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype.

Results: Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so.

Interpretation: This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078025PMC
April 2020

Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients.

Arthritis Res Ther 2020 01 8;22(1). Epub 2020 Jan 8.

Department of Medicine, McGill University, Montreal, Canada.

Objective: To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy.

Methods: Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies.

Results: A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment.

Conclusion: While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-019-2093-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950801PMC
January 2020

A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01.

BMC Cancer 2019 Dec 27;19(1):1250. Epub 2019 Dec 27.

Division of Hemato-Oncology, Department of Pediatrics, McGill University Health Center, Montreal Children's Hospital, Montreal, QC, Canada.

Background: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study.

Methods: The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.

Discussion: Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN.

Trial Registration: ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-6442-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935133PMC
December 2019

Stalled developmental programs at the root of pediatric brain tumors.

Nat Genet 2019 12 25;51(12):1702-1713. Epub 2019 Nov 25.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0531-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885128PMC
December 2019

Astrocytes in the Pathogenesis of Multiple Sclerosis: An In Situ MicroRNA Study.

J Neuropathol Exp Neurol 2019 12;78(12):1130-1146

Department of Pathology, The Ottawa Hospital, University of Ottawa.

Astrocytes are increasingly recognized as active contributors to the disease process in multiple sclerosis (MS), rather than being merely reactive. We investigated the expression of a selected microRNA (miRNA) panel that could contribute both to the injury and to the recovery phases of the disease. Individual astrocytes were laser microdissected from brain sections. We then compared the miRNAs' expressions in MS and control brain samples at different lesional stages in white versus grey matter regions. In active MS lesions, we found upregulation of ischemia-related miRNAs in white but not grey matter, often with reversion to the normal state in inactive lesions. In contrast to our previous findings on MS macrophages, expression of 2 classical inflammatory-related miRNAs, miRNA-155 and miRNA-146a, was reduced in astrocytes from active and chronic active MS lesions in white and grey matter, suggesting a lesser direct pathogenetic role for these miRNAs in astrocytes. miRNAs within the categories regulating aquaporin4 (-100, -145, -320) and glutamate transport/apoptosis/neuroprotection (-124a, -181a, and -29a) showed some contrasting responses. The regional and lesion-stage differences of expression of these miRNAs indicate the remarkable ability of astrocytes to show a wide range of selective responses in the face of differing insults and phases of resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlz098DOI Listing
December 2019

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Cancer Cell 2019 07;36(1):51-67.e7

Children's Brain Tumor Research Centre, Queen's Medical Centre University of Nottingham, Nottingham NG72UH, UK.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2019.06.002DOI Listing
July 2019

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

Genet Med 2019 11 16;21(11):2521-2531. Epub 2019 May 16.

Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.

Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.

Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0532-zDOI Listing
November 2019

Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.

Cancer Cell 2019 05;35(5):782-797.e8

Department of Pediatrics, Division of Hematology and Oncology, Texas Children's Cancer and Hematology Centers, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521975PMC
May 2019

Seizures in Pediatric Patients With Primary Brain Tumors.

Pediatr Neurol 2019 08 28;97:50-55. Epub 2019 Mar 28.

Division of Child Neurology, Department of Pediatrics, Montreal, Québec, Canada. Electronic address:

Background: Seizures are one of the most common symptoms of pediatric brain tumors. The purpose of this study was to define seizures related to primary central nervous system tumors and to identify risk factors predictive of seizure occurrence and recurrence.

Methods: We reviewed the records of children treated from January 1, 2004, to January 1, 2018 and collected data including age, gender, tumor location, histology, extent of initial resection, seizure characteristics, treatment modalities, recurrence, and seizure control. A binomial logistic regression was performed to determine the risk factors of seizure occurrence.

Results: During the observation period, 348 children were diagnosed with a primary brain tumor. The median age at diagnosis was 7.8 years, and the median follow-up interval was 3.9 years. There were 196 boys (56.3%). In our cohort, a total of 70 children (20.1%) experienced seizures. Most of them (64.3%) had cortical tumors. All patients with dysembryoplastic neuroepithelial tumors and 81.8% of patients with glioneuronal tumors presented seizures. Risk factors associated with an increased risk for seizures included cortical location, tumor recurrence, and age at diagnosis. Thirty-nine (86.7%) patients with seizures at diagnosis were seizure free at last follow-up (Engel 1). Significantly more patients (69.6%) with a gross total resection were withdrawn from their antiepileptic drugs when compared with those with subtotal resection (27.3%, P = 0.007).

Conclusions: Our study is the largest cohort in children with tumor-related seizures and brings new insight in terms of seizure risk according to tumor types and evolution following treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2019.03.020DOI Listing
August 2019

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers.

JAMA Netw Open 2019 04 5;2(4):e192906. Epub 2019 Apr 5.

Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Québec, Canada.

Importance: Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-to-treat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases.

Objective: To assess the feasibility of identifying potentially actionable mutations using next-generation sequencing-based assays in a clinically relevant time frame.

Design, Setting, And Participants: This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Québec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board.

Main Outcomes And Measures: Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies.

Results: A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken.

Conclusions And Relevance: Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, including targeted therapy and clinically relevant information of diagnostic, prognostic, and monitoring significance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2019.2906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487576PMC
April 2019

H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis.

Nat Commun 2019 03 19;10(1):1262. Epub 2019 Mar 19.

Department of Biochemistry and Biophysics, and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09140-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425035PMC
March 2019

Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum.

Am J Med Genet A 2019 03 16;179(3):386-396. Epub 2019 Jan 16.

The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61025DOI Listing
March 2019

ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features.

Clin Neuropathol 2019 Mar/Apr;38(2):59-73

Introduction: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA.

Materials And Methods: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated , IDH, , , , , 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry.

Results: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for , and had no IDH/ mutations, nor amplification. Two of 5 tumors showed duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed /6q23 deletion.

Conclusion: We confirm ATRX protein loss suggestive of alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.
.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5414/NP301105DOI Listing
May 2019

Mucolipidosis type IV in a child.

J AAPOS 2018 Dec 16;22(6):469-471. Epub 2018 Aug 16.

Department of Ophthalmology, Centre hospitalier universitaire Sainte-Justine, Montréal. Electronic address:

Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder with psychomotor developmental delay, visual impairment, and achlorhydria. A mutation in the MCOLN1 gene causes an alteration of the protein mucolipin-1 that results in the accumulation of lipids and proteins in cytoplasmic vacuoles derived from lysosomes. Visual impairment results mainly from corneal clouding and retinal degeneration. The involvement of the corneal epithelium has been proposed following clinical observation and confirmed by ultrastructural studies of the cornea. We present the case of a child of French Canadian origin affected by mucolipidosis type IV who showed abnormal optical coherence tomography imaging of the cornea, typical skin cell inclusions on electronic microscopy, and a novel pathogenic mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaapos.2018.04.011DOI Listing
December 2018

Trametinib for progressive pediatric low-grade gliomas.

J Neurooncol 2018 Nov 10;140(2):435-444. Epub 2018 Aug 10.

Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada.

Introduction: Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors.

Methods: Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed.

Results: The median age at diagnosis was 2.3 years (y) old [range 11 months (m)-8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1-4). The median time on treatment was 11 m (range 4-20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life.

Conclusion: Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-018-2971-9DOI Listing
November 2018

Embryonal Tumor with Multilayered Rosettes Presenting with Intermittent Third Nerve Palsy.

Can J Neurol Sci 2018 07 8;45(4):483-484. Epub 2018 Jun 8.

6Department of Pediatrics,Division of Child NeurologyCentre Hospitalier Universitaire Sainte-JustineMontreal,Quebec,Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2018.23DOI Listing
July 2018

Multiple DICER1-related tumors in a child with a large interstitial 14q32 deletion.

Genes Chromosomes Cancer 2018 05 10;57(5):223-230. Epub 2018 Feb 10.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

Germ-line interstitial deletions involving the 14q32 chromosomal region, resulting in 14q32 deletion syndrome, are rare. DICER1 is a recently described cancer-predisposition gene located at 14q32.13. We report the case of a male child with a ∼5.8 Mbp 14q32.13q32.2 germ-line deletion, which included the full DICER1 locus. We reviewed available clinical and pathological material, and conducted genetic analyses. In addition to having congenital dysmorphic features, the child developed multiple DICER1 syndrome-related tumors before age 5 y: a pediatric cystic nephroma (pCN), a ciliary body medulloepithelioma (CBME), and a small lung cyst (consistent with occult pleuropulmonary blastoma Type I/Ir cysts seen in DICER1 mutation carriers). He also developed a cerebral spindle-cell sarcoma with myogenous differentiation. Our investigations revealed that the deletion encompassed 31 protein-coding genes. In addition to the germ-line DICER1 deletion, somatic DICER1 RNase IIIb mutations were found in the CBME (c.5437G > A, p.E1813K), pCN (c.5425G > A, p.G1809R), and sarcoma (c.5125G > A, p.D1709N). The sarcoma also harbored a somatic TP53 mutation: c.844C > T, p.R282W. Additional copy number alterations were identified in the CBME and sarcoma using an OncoScan array. Among the 8 cases with molecularly-defined 14q32 deletions involving DICER1 and for whom phenotypic information is available, our patient and one other developed DICER1-related tumors. Biallelic DICER1 mutations have not previously been reported to cause cerebral sarcoma, which now may be considered a rare manifestation of the DICER1 syndrome. Our study shows that DICER1-related tumors can occur in children with 14q32 deletions and suggests surveillance for such tumors may be warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22523DOI Listing
May 2018

Brainstem angiocentric gliomas with MYB-QKI rearrangements.

Acta Neuropathol 2017 Oct 12;134(4):667-669. Epub 2017 Aug 12.

Department of Pathology, Sainte-Justine Hospital, Université de Montréal, Montréal, QC, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-017-1763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556888PMC
October 2017

Two Cases of Retinoblastoma Invading the Optic Nerve Sheath.

J Pediatr Ophthalmol Strabismus 2016 Sep 24;53:e51-e53. Epub 2016 Sep 24.

The authors report two cases of retinoblastoma with extension along the optic nerve sheath with negative surgical margins, a pattern not considered in current classifications but suggesting a high risk of metastasis. Both patients were treated with adjuvant chemotherapy alone and remain free of extraocular disease 15 and 22 months later. [J Pediatr Ophthalmol Strabismus. 2016;53:e51-e53.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/01913913-20160823-02DOI Listing
September 2016

Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.

Nat Commun 2016 Apr 6;7:11185. Epub 2016 Apr 6.

Research Center for Genetic Medicine, Children's National Health System, Washington, District Of Columbia 20010, USA.

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms11185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823825PMC
April 2016

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.

Acta Neuropathol 2016 06 26;131(6):847-63. Epub 2016 Feb 26.

Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-016-1549-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039033PMC
June 2016

SYK is a target of lymphocyte-derived microparticles in the induction of apoptosis of human retinoblastoma cells.

Apoptosis 2015 Dec;20(12):1613-22

Departments of Pediatrics, Hematology-Oncology and Pharmacology, University of Montréal, Montreal, QC, Canada.

Retinoblastoma (Rb) is an aggressive childhood cancer of the developing retina. This disease is associated with epigenetic deregulation of several cancer pathways including upregulation of the proto-oncogene spleen tyrosine kinase (SYK). We have previously demonstrated that lymphocyte-derived microparticles (LMPs) possess strong cytotoxic effect on cancer cells. This report demonstrated that LMPs have potent pro-apoptotic properties on human Rb cells, which was associated with a strong reduction of SYK expression. Perturbing SYK activity in Rb cells induced cell apoptosis and upregulated expression of p53 and p21. Interestingly, inhibition of p53 or knockdown of p21, abolished LMP-induced caspase-3 activity and cell death. Blocking oxidized phospholipid-rich LMPs with a specific antibody significantly prevented LMP-induced Rb apoptosis and reversed the expression patterns of SYK, p53, p21. In summary, our results suggest that LMPs are important pro-apoptotic regulators for Rb cells through reduction of SYK expression and upregulation of the p53-p21 pathway which ultimately activates caspase-3. These data may open unexpected avenues for the development of LMPs as a novel therapeutic strategy that would be particularly useful and relevant for the treatment of Rb.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10495-015-1177-2DOI Listing
December 2015

Adult brainstem gliomas: Correlation of clinical and molecular features.

J Neurol Sci 2015 18;353(1-2):92-7. Epub 2015 Apr 18.

Division of Neuro-oncology, The Ohio State University Comprehensive Cancer Center, 320 W 10th Avenue, Starling Loving Hall Suite M410, Columbus, OH 43210, United States.

Background: Brainstem gliomas are rare in adults and overall have superior survival outcomes compared to pediatric brainstem gliomas.

Patients And Methods: We conducted a retrospective data and tissue analysis of all adult patients (≥ 18 years old) with World Health Organization (WHO) Grade II, III, and IV brainstem gliomas in the University of Texas MD Anderson Cancer Center institutional database from 1990 to 2012.

Results: We identified 143 cases in adults ages 18 and over. There were 28 glioblastomas, 43 anaplastic astrocytomas, 15 diffuse astrocytomas, and 11 gliomas not otherwise specified, and in 46 cases the diagnosis was made radiographically. 128 (89.5%) cases were classified radiographically as diffuse and of the focal tumors, 9 of the 15 were WHO Grade III or IV tumors. Increasing tumor grade and contrast enhancement were associated with significantly reduced overall survival. The median overall survival for the entire cohort was 32.1 months similar to previously published studies. Two of 25 grade II and III tumors, and 1 of 17 glioblastomas had IDH1 mutations on immunohistochemical testing. Nine cases had sufficient tissue for mutation profiling, 1 case had a BRAF V600E mutation and 2 had 2 PIK3CA mutations.

Conclusions: Survival outcomes for adult WHO Grade II to IV brainstem gliomas were similar to supratentorial IDH1 wild-type tumors of similar grade and histology. Potentially actionable mutations can be identified from small biopsy samples in a subset of adult brainstem gliomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2015.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782610PMC
February 2016