Browsing by Author "Karamchandani, Jason"

Now showing 1 - 3 of 3
  • Thumbnail Image
    ItemOpen Access
    Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
    (2022-12-12) Zwaig, Melissa; Baguette, Audrey; Hu, Bo; Johnston, Michael; Lakkis, Hussein; Nakada, Emily M.; Faury, Damien; Juretic, Nikoleta; Ellezam, Benjamin; Weil, Alexandre G.; Karamchandani, Jason; Majewski, Jacek; Blanchette, Mathieu; Taylor, Michael D.; Gallo, Marco; Kleinman, Claudia L.; Jabado, Nada; Ragoussis, Jiannis
    Abstract Background Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway. RAF-fusions are the most common genetic alterations identified in JPAs, with the prototypical KIAA1549-BRAF fusion leading to loss of BRAF’s auto-inhibitory domain and subsequent constitutive kinase activation. JPAs are highly vascular and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. This can result in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq. Methods To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level. Results Integration of these datasets allowed the identification and detailed characterization of two novel BRAF fusion partners, PTPRZ1 and TOP2B, in addition to the canonical fusion with partner KIAA1549. Additionally, our Hi-C datasets enabled investigations of 3D genome architecture in JPAs which showed a high level of correlation in 3D compartment annotations between JPAs compared to other pediatric tumors, and high similarity to normal adult astrocytes. We detected interactions between BRAF and its fusion partners exclusively in tumor samples containing BRAF fusions. Conclusions We demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution. We suggest that linked-reads and Hi-C could be used in clinic for the detection and characterization of JPAs.
  • Thumbnail Image
    ItemOpen Access
    Myositis with prominent B-cell aggregates causing shrinking lung syndrome in systemic lupus erythematosus: a case report
    (2022-02-16) Roy, Flavie; Korathanakhun, Pat; Karamchandani, Jason; Dubé, Bruno-Pierre; Landon-Cardinal, Océane; Routhier, Nathalie; Peyronnard, Caroline; Massie, Rami; Leclair, Valérie; Meyer, Alain; Bourré-Tessier, Josiane; Satoh, Minoru; Fritzler, Marvin J.; Senécal, Jean-Luc; Hudson, Marie; O’Ferrall, Erin K.; Troyanov, Yves; Ellezam, Benjamin; Makhzoum, Jean-Paul
    Abstract Background Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and diaphragmatic weakness in a dyspneic patient. Chest wall dysfunction secondary to pleuritis is the most commonly proposed cause. In this case report, we highlight a new potential mechanism of SLS in SLE, namely diaphragmatic weakness associated with myositis with CD20 positive B-cell aggregates. Case presentation A 51-year-old Caucasian woman was diagnosed with SLE and secondary Sjögren’s syndrome based on a history of pleuritis, constrictive pericarditis, polyarthritis, photosensitivity, alopecia, oral ulcers, xerophthalmia and xerostomia. Serologies were significant for positive antinuclear antibodies, anti-SSA, lupus anticoagulant and anti-cardiolopin. Blood work revealed a low C3 and C4, lymphopenia and thrombocytopenia. She was treated with with low-dose prednisone and remained in remission with oral hydroxychloroquine. Seven years later, she developed mild proximal muscle weakness and exertional dyspnea. Pulmonary function testing revealed a restrictive pattern with small lung volumes. Pulmonary imaging showed elevation of the right hemidiaphragm without evidence of interstitial lung disease. Diaphragmatic ultrasound was suggestive of profound diaphragmatic weakness and dysfunction. Based on these findings, a diagnosis of SLS was made. Her proximal muscle weakness was investigated, and creatine kinase (CK) levels were normal. Electromyography revealed fibrillation potentials in the biceps, iliopsoas, cervical and thoracic paraspinal muscles, and complex repetitive discharges in cervical paraspinal muscles. Biceps muscle biopsy revealed dense endomysial lymphocytic aggregates rich in CD20 positive B cells, perimysial fragmentation with plasma cell-rich perivascular infiltrates, diffuse sarcolemmal upregulation of class I MHC, perifascicular upregulation of class II MHC, and focal sarcolemmal deposition of C5b-9. Treatment with prednisone 15 mg/day and oral mycophenolate mofetil 2 g/day was initiated. Shortness of breath and proximal muscle weakness improved significantly. Conclusion Diaphragmatic weakness was the inaugural manifestation of myositis in this patient with SLE. The spectrum of myologic manifestations of myositis with prominent CD20 positive B-cell aggregates in SLE now includes normal CK levels and diaphragmatic involvement, in association with SLS.
  • Thumbnail Image
    ItemOpen Access
    Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients
    (2020-01-08) Meyer, Alain; Troyanov, Yves; Drouin, Julie; Oligny-Longpré, Geneviève; Landon-Cardinal, Océane; Hoa, Sabrina; Hervier, Baptiste; Bourré-Tessier, Josiane; Mansour, Anne-Marie; Hussein, Sara; Morin, Vincent; Rich, Eric; Goulet, Jean-Richard; Chartrand, Sandra; Hudson, Marie; Nehme, Jessica; Makhzoum, Jean-Paul; Zarka, Farah; Villeneuve, Edith; Raynauld, Jean-Pierre; Landry, Marianne; O’Ferrall, Erin K; Ferreira, Jose; Ellezam, Benjamin; Karamchandani, Jason; Larue, Sandrine; Massie, Rami; Isabelle, Catherine; Deschênes, Isabelle; Leclair, Valérie; Couture, Hélène; Targoff, Ira N; Fritzler, Marvin J; Senécal, Jean-Luc
    Abstract 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.