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| − | ==Primary Author==
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| − | Linda D Cooley, MD, MBA
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| − | ==H3 K27M-mutant glioma==
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| − | __TOC__
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| − | ==Cancer Category/Type==
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| − | An infiltrative midline high-grade glioma with predominantly astrocytic differentiation and a K27M mutation in either H3F3A or HIST1H3B/C 1.
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| − | H3 K27M-mutant diffuse midline glioma predominates in children, but can be seen in adults. It is a grade IV tumor even when mitotic figures, microvascular proliferation and necrosis are absent.
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| − | In adults, this is a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis2.
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| − | ==Cancer Sub-Classification / Subtype==
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| − | Histone H3.3 is a protein that in humans is encoded by the H3F3A gene. Mutations of H3F3A are linked to certain cancers. p.Lys27Met were discovered in Diffuse Intrinsic Pontine Glioma (DIPG), where they are present 65-75% of tumors and confer a worse prognosis. p.Lys27Met alterations in HIST1H3B and HIST1H3C, which code for histone H3.1 have been reported in ~10% of DIPG7,8.==
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| − | Adults2: Predominately younger adults (<40 yrs); but can occur at any age
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| − | 2-7.5% of adult IDH wild-type astrocytomas
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| − | 37.5-66% of adult midline gliomas
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| − | Pediatric & young adult3: Majority of diffuse intrinsic pontine gliomas (DIPG), thalamic glioblastomas (GBM)
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| − | Median age 5-11 years with pontine tumors arising at ~7 years and thalamic tumors at ~11 years
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| − | ==Clinical Features==
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| − | The clinical presentation – brainstem dysfunction, CSF obstruction, increase intracranial pressure, ataxia, cranial nerve injury, progressive sensorimotor deficits
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| − | ==Midline locations: brainstem (midbrain, pons, floor 4th ventricle, medulla oblongata), spinal cord, thalamus; Other locations: hypothalamus, pineal region, cerebellum==
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| − | ==Histopathology – astrocytic morphology – can range from diffuse low-grade glioma to high grade glioma.
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| − | H3 K27M-mutant gliomas can display a broad spectrum of histological features, including giant, epithelioid, and rhabdoid cells; primitive neuroectodermal tumor–like foci; ependymal-like areas; sarcomatous transformation, as well as features that may wrongly suggest circumscribed gliomas such as neuropil-like islands, pilomyxoid features, ganglionic differentiation, and pleomorphic xanthoastrocytoma-like areas.
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| − | ==
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| − | Positive (universal) H3F3A K27M, NCAM1, S100, Oligo2
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| − | Positive (subset) GFAP variable, MAP2 common, synaptophysin may be focal, TP53, MGMT
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| − | Negative (universal) Chromogranin-A, NeuN, IDH, EGFR
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| − | Negative (subset) ATRX
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| − | ==
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| − | {| class="wikitable sortable"
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| − | ! Finding !! Marker
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| − | |Positive (universal) || CD1
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| − | |Positive (subset) || CD2
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| − | |Negative (universal) || CD3
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| − | |-
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| − | |Negative (subset) || CD4
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| − | |}
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| − | ===Characteristic Aberrations / Patterns
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| − | H3-K27M mutation defines the entity. K27M mutation occurs in either of 2 genes, H3F3A or HIST1H3B, which encode the histone H3 variants, H3.3 and H3.1, respectively3.
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| − | Cooperating genetic alterations include: TP53 and ATRX mutations. A subset of K27M+ DIPGs have ACVR1 missense mutations (encodes the activin A receptor type-1 transmembrane protein, that lead to activation of the BMP-TGF signaling pathway). Other alterations found in K27M+ DIPGs include PIK3CA mutation, PDGFRA mutation or amplification, PPM1D mutation, and amplification of cell cycle genes including CCND1, CDK4 and CDK63.
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| − | ===
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| − | ==Chromosomal Rearrangements (Gene Fusions)==
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| − | {| class="wikitable sortable"
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| − | ! Chromosomal Rearrangement !! Genes in Fusion (5’ or 3’ Segments) !! Pathogenic Derivative !! Prevalence
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| − | |t(9;22) || BCR-ABL1 || der(22) || 5%
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| − | |t(8;21) || RUNX1-RUNXT1 || der(8) || 5%
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| − | |}
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| − | ===Additional Description:===
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| − | ==Characteristic Chromosomal Aberrations / Patterns==
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| − | ==Genomic Gain/Loss/LOH==
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| − | {| class="wikitable sortable"
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| − | ! Chromosome Number !! Gain/Loss/Amp/LOH !! Region
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| − | | 8 || Gain || chr8:0-1000000
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| − | |-
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| − | |7 || Loss || chr7:0-1000000
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| − | |}
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| − | ===Additional Description:===
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| − | ==Gene Mutations (SNV/INDEL)==
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| − | {| class="wikitable sortable"
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| − | ! Gene !! Mutation !! Oncogene/Tumor Suppressor/Other !! Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) !! Prevalence (COSMIC/TCGA/Other)
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| − | | TP53 || R273H || Tumor Suppressor || LOF || 20%
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| − | |}
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| − | ===Additional Description:===
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| − | *Other Mutations
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| − | *Concomitant Mutations
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| − | *Secondary Mutations
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| − | *Mutually Exclusive
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| − | ==Epigenomics (Methylation)==
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| − | ==Genes and Main Pathways Involved==
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| − | ==Diagnostic Testing Methods==
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| − | ==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
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| − | ==Familial Forms==
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| − | ==Other Information==
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| − | ==Links==
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| − | ==References==
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| − | === Reference Example, BOOK ===
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| − | #Arber DA, Brunning RD, Le Beau MM, Falini B, Vardiman JW, Porwit A, Thiele J, Bloomfield CD (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.
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| − | === Reference Example, Journal Article ===
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| − | #Li Y, Mehta PK, Nizetic D, Kaneko Y, Chan GCF, Chan LC, Squire J, Scherer SW and Hitzler JK (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.
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| | K27M-mutant glioma | | K27M-mutant glioma |
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