نتائج البحث - "Devine, Patrick"

1

دورية أكاديمية

TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature.

المؤلفون: Xiao, Andrew, Shahmarvand, Nahid, Nagy, Alexandra, Kumar, Jyoti, Van Ziffle, Jessica, Devine, Patrick, Huang, Franklin, Lezama, Lhara, Li, Peng, Ohgami, Robert S

مصطلحات موضوعية: ALK, ALK fusion, ALK translocation, ALK+ large B-cell lymphoma, TFG, Cancer, Rare Diseases, Lymphoma, Genetics, Hematology, Aetiology, 2.1 Biological and endogenous factors, ALK plus large B-cell lymphoma, Oncology and Carcinogenesis

الوصف: Anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma (ALK+ LBCL) is an aggressive and rare subtype of B-cell lymphoma. Patients typically present with advanced clinical stage disease and do not respond to conventional chemotherapy; the median overall survival is 1.8 years. The genetic landscape of this entity remains poorly understood. Here we report a unique case of ALK+ LBCL harbouring a rare TFG::ALK fusion. Targeted next-generation sequencing showed no significant single nucleotide variants, insertions/deletions, or other structural variants beyond the TFG::ALK fusion; deep deletions of FOXO1, PRKCA, and the MYB locus were also detected. Our case report draws attention to this rare disease, highlights a need for larger genetic profiling studies, and focuses on the pathogenesis and potential therapeutic targets of this aggressive disease. To our knowledge, this is the first report of a TFG::ALK fusion in ALK+ LBCL.

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2

دورية أكاديمية

Targeted Next-Generation Sequencing Reveals Divergent Clonal Evolution in Components of Composite Pleomorphic Xanthoastrocytoma-Ganglioglioma

المصدر: Journal of Neuropathology & Experimental Neurology. 81(8)

الوصف: Composite pleomorphic xanthoastrocytoma-ganglioglioma (PXA-GG) is an extremely rare central nervous system neoplasm with 2 distinct but intermingled components. Whether this tumor represents a "collision tumor" of separate neoplasms or a monoclonal neoplasm with divergent evolution is poorly understood. Clinicopathologic studies and capture-based next generation sequencing were performed on extracted DNA from all available PXA-GG at 2 medical centers. Five PXA-GG were diagnosed in 1 male and 4 female patients ranging from 13 to 25 years in age. Four arose within the cerebral hemispheres; 1 presented in the cerebellar vermis. DNA was sufficient for analysis in 4 PXA components and 3 GG components. Four paired PXA and GG components harbored BRAF p.V600E hotspot mutations. The 4 sequenced PXA components demonstrated CDKN2A homozygous deletion by sequencing with loss of p16 (protein product of CDKN2A) expression by immunohistochemistry, which was intact in all assessed GG components. The PXA components also demonstrated more frequent copy number alterations relative to paired GG components. In one PXA-GG, shared chromosomal copy number alterations were identified in both components. Our findings support divergent evolution of the PXA and GG components from a common BRAF p.V600E-mutant precursor lesion, with additional acquisition of CDKN2A homozygous deletion in the PXA component as is typically seen in conventional PXA.

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3

دورية أكاديمية

APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Genetics, Rare Diseases, Cancer, Clinical Research, Good Health and Well Being, bladder cancer, APOBEC mutational signature, tumor mutational burden, next-generation sequencing, urothelial cancer, hypermutated, biomarkers, immune checkpoint inhibitor, Clinical sciences, Oncology and carcinogenesis

الوصف: IntroductionTumor mutational burden (TMB) and APOBEC mutational signatures are potential prognostic markers in patients with advanced urothelial carcinoma (aUC). Their utility in predicting outcomes to specific therapies in aUC warrants additional study.MethodsWe retrospectively reviewed consecutive UC cases assessed with UCSF500, an institutional assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM), defined as having TMB ≥10 mutations/Mb, were also assessed for APOBEC mutational signatures, while non-HM (NHM) tumors were not assessed due to low TMB. The logrank test was used to determine if there were differences in overall survival (OS) and progression-free survival (PFS) among patient groups of interest.ResultsAmong 75 aUC patients who had UCSF500 testing, 46 patients were evaluable for TMB, of which 19 patients (41%) had HM tumors and the rest had NHM tumors (27 patients). An additional 29 patients had unknown TMB status. Among 19 HM patients, all 16 patients who were evaluable for analysis had APOBEC signatures. HM patients (N=19) were compared with NHM patients (N=27) and had improved OS from diagnosis (125.3 months vs 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.04). Patients with APOBEC (N=16) were compared with remaining 56 patients, comprised of 27 NHM patients and 29 patients with unknown TMB, showing APOBEC patients to have improved OS from diagnosis (125.3 months vs 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy.ConclusionsIn a large, single-institution aUC cohort assessed with UCSF500, an institutional NGS panel, HM tumors were common and all such tumors that were evaluated for mutational signature analysis had APOBEC signatures. APOBEC signatures and high TMB were prognostic of improved OS from diagnosis and both analyses also predicted inferior outcomes with chemotherapy treatment.

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4

دورية أكاديمية

Sarcomatous Meningioma: Diagnostic Pitfalls and the Utility of Molecular Testing.

المؤلفون: Lucas, Calixto-Hope G, Devine, Patrick, Solomon, David A, Giannini, Caterina, Reifenberger, Guido, Dahiya, Sonika, Caccamo, Dario, Perry, Arie

المصدر: Journal of Neuropathology & Experimental Neurology. 80(8)

مصطلحات موضوعية: Rare Diseases, Brain Disorders, Brain Cancer, Cancer, Adult, Aged, Biomarkers, Tumor, Diagnosis, Differential, Female, Humans, Meningeal Neoplasms, Meningioma, Neurofibromin 2, Sarcoma, Anaplastic, Molecular, Neuropathology, Sarcomatous, Clinical Sciences, Neurosciences, Neurology & Neurosurgery

الوصف: Anaplastic meningiomas can have a sarcomatous appearance on histology but true sarcomatous (metaplastic) differentiation is rare. These tumors follow an aggressive clinical course with recurrence and poor clinical outcomes. Due to significant overlap in morphology and immunohistochemical profiles, distinguishing between sarcomatous transformation of a meningioma and a true sarcoma can be challenging. Here, we outline potential diagnostic pitfalls and the utility of ancillary molecular testing in 3 patients diagnosed with sarcomatous meningiomas. We report loss of typical meningothelial markers in sarcomatous meningiomas. Ancillary molecular testing can support the diagnosis of sarcomatous meningioma when a molecular signature consistent with meningioma is seen, such as inactivation of the NF2 gene. Recognition of this rare transformation in meningioma can prevent a misdiagnosis of a primary sarcoma, whether sporadic or radiation-induced from prior treatment of a more classic meningioma.

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5

دورية أكاديمية

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

المصدر: Obstetrical & Gynecological Survey. 76(3)

مصطلحات موضوعية: Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine

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الوصول الحر: https://escholarship.org/uc/item/2v62d0jgTest

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6

دورية أكاديمية

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

المصدر: New England Journal of Medicine. 383(18)

مصطلحات موضوعية: Reproductive Medicine, Biomedical and Clinical Sciences, Health Sciences, Brain Disorders, Genetics, Pediatric, Clinical Research, Human Genome, Genetic Testing, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Reproductive health and childbirth, Good Health and Well Being, Female, Genetic Variation, Humans, Hydrops Fetalis, Pregnancy, Prenatal Diagnosis, Prognosis, Exome Sequencing, University of California Fetal–Maternal Consortium, University of California, San Francisco Center for Maternal–Fetal Precision Medicine, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences

الوصف: BackgroundThe cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.MethodsWe evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.ResultsIn 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.ConclusionsIn this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).

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7

دورية أكاديمية

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition

المؤلفون: Mondal, Gourish, Lee, Julieann C, Ravindranathan, Ajay, Villanueva-Meyer, Javier E, Tran, Quynh T, Allen, Sariah J, Barreto, Jairo, Gupta, Rohit, Doo, Pamela, Van Ziffle, Jessica, Onodera, Courtney, Devine, Patrick, Grenert, James P, Samuel, David, Li, Rong, Metrock, Laura K, Jin, Lee-way, Antony, Reuben, Alashari, Mouied, Cheshier, Samuel, Whipple, Nicholas S, Bruggers, Carol, Raffel, Corey, Gupta, Nalin, Kline, Cassie N, Reddy, Alyssa, Banerjee, Anu, Hall, Matthew D, Mehta, Minesh P, Khatib, Ziad, Maher, Ossama M, Brathwaite, Carole, Pekmezci, Melike, Phillips, Joanna J, Bollen, Andrew W, Tihan, Tarik, Lucas, John T, Broniscer, Alberto, Berger, Mitchel S, Perry, Arie, Orr, Brent A, Solomon, David A

المصدر: Acta Neuropathologica. 139(6)

الوصف: Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.

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8

دورية أكاديمية

Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features.

المصدر: Brain pathology (Zurich, Switzerland). 30(3)

مصطلحات موضوعية: Lateral Ventricles, Septum Pellucidum, Corpus Callosum, Humans, Glioma, Brain Neoplasms, Cerebral Ventricle Neoplasms, Receptor, Platelet-Derived Growth Factor alpha, Magnetic Resonance Imaging, Mutation, Adolescent, Adult, Aged, Child, Female, Male, Young Adult, High-Throughput Nucleotide Sequencing, White Matter, PDGFRA, DNT-like tumor of the septum pellucidum, corpus callosum, dysembryoplastic neuroepithelial tumor, lateral ventricle, molecular neuro-oncology, molecular neuropathology, myxoid glioneuronal tumor, periventricular white matter, platelet-derived growth factor receptor alpha, septal DNT, septum pellucidum, Neurosciences, Brain Disorders, Cancer, PDGFRA, Clinical Sciences, Neurology & Neurosurgery

الوصف: "Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.

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9

دورية أكاديمية

Gliomas arising in the setting of Li-Fraumeni syndrome stratify into two molecular subgroups with divergent clinicopathologic features

المصدر: Acta Neuropathologica. 139(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Adolescent, Adult, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Glioma, Humans, Li-Fraumeni Syndrome, Male, Tumor Suppressor Protein p53, Young Adult, Clinical Sciences, Neurology & Neurosurgery

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الوصول الحر: https://escholarship.org/uc/item/6d89g89fTest

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10

دورية أكاديمية

PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

المؤلفون: Calixto-Hope, Lucas, Lee, Julieann, Sloan, Emily, Hofmann, Jeffrey, Van Ziffle, Jessica, Onodera, Courtney, Grenert, James, Devine, Patrick, Kline, Cassie, Banerjee, Anu, Clarke, Jennifer, Taylor, Jennie, Ann Oberheim-Bush, Nancy, Buerki, Robin, Butowski, Nicholas, Chang, Susan, McDermott, Mike, Aghi, Manish, Theodosopoulos, Philip, Hervey-Jumper, Shawn, Berger, Mitchel, Raffel, Corey, Gupta, Nalin, Kleinschmidt-DeMasters, Bette, Wood, Matthew, Grafe, Marjorie, Guo, Hua, Sun, Peter, Torkildson, Joseph, Cooney, Tabitha, Fata, Cynthia, Scharnhorst, David, Samuel, David, Bannykh, Serguei, Khatib, Ziad, Maher, Ossama, Chamyan, Gabriel, Pelaez, Liset, Brathwaite, Carole, Jin, Lee-way, Lechpammer, Mirna, Born, Donald, Vogel, Hannes, Lee, Han, Phillips, Joanna, Pekmezci, Melike, Bollen, Andrew, Tihan, Tarik, Perry, Arie, Solomon, David

المصدر: Neuro-Oncology. 21(Supplement_6)

مصطلحات موضوعية: Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.

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الوصول الحر: https://escholarship.org/uc/item/4dr7x634Test

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