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2.
Sci Rep ; 9(1): 1903, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760837

RESUMO

To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.


Assuntos
Neoplasias Encefálicas/patologia , Desmetilação do DNA , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Proteínas de Ciclo Celular/genética , Ilhas de CpG , Progressão da Doença , Glioma/genética , Glioma/mortalidade , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Mutação , Gradação de Tumores , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/genética , Regulação para Cima
3.
Acta Neuropathol Commun ; 5(1): 18, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28270234

RESUMO

Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.


Assuntos
Neoplasias Encefálicas/genética , Epigênese Genética , Recidiva Local de Neoplasia/genética , Oligodendroglioma/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Estudos de Coortes , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Oligodendroglioma/diagnóstico por imagem , Oligodendroglioma/patologia , Oligodendroglioma/terapia , Adulto Jovem
4.
Histopathology ; 69(2): 260-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26741321

RESUMO

AIMS: We performed an immunohistochemical analysis of alpha-thalassaemia/mental retardation syndrome X-linked (ATRX) expression in adult diffuse gliomas, with reference to clinicopathological and genetic features, to determine the utility of this analysis in diagnostic practice. METHODS AND RESULTS: A total of 193 adult diffuse gliomas underwent immunohistochemical analysis. In areas in which internal controls, neurones, glia and blood vessels were properly stained, the ATRX immunoreactivity of tumour cells was either almost totally absent or completely retained in all cases. There was perfect concordance between the immunohistochemical results and ATRX mutation status, which was known in 19 cases. ATRX loss was observed in 54.5, 30.8 and 0.0% of grades II/III astrocytomas, oligoastrocytomas and oligodendrogliomas, respectively, and 12.7% of glioblastomas. In grades II/III gliomas, most ATRX-loss cases (92.3%) had IDH1/2 mutations. ATRX loss was associated significantly with TP53 mutation and p53 overexpression (P < 0.001), but was never accompanied by 1p/19q co-deletion. IDH1/2 mutation in ATRX-loss tumours was less frequent in glioblastomas than in grades II/III gliomas (P < 0.001). Further, there was no significant association between ATRX loss and p53 overexpression in glioblastomas. ATRX-loss glioblastomas affected younger patients (P < 0.001) and occurred more frequently in locations other than the cerebral hemispheres (P = 0.006). Most grades II/III gliomas (93.3%) were categorized into three molecular subtypes based on the status of IDH1/2 mutation, ATRX immunohistochemistry and 1p/19q co-deletion. CONCLUSIONS: Distinct histological and molecular characteristics of adult diffuse gliomas with and without ATRX immunoreactivity indicate the utility of ATRX immunohistochemistry in diagnostic practice.


Assuntos
Astrocitoma/diagnóstico , DNA Helicases/metabolismo , Glioblastoma/diagnóstico , Glioma/diagnóstico , Proteínas Nucleares/metabolismo , Oligodendroglioma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/metabolismo , DNA Helicases/genética , Feminino , Glioblastoma/metabolismo , Glioma/metabolismo , Humanos , Imuno-Histoquímica , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Proteínas Nucleares/genética , Oligodendroglioma/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X , Adulto Jovem
5.
Acta Neuropathol ; 129(4): 597-607, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25724300

RESUMO

Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/complicações , Distúrbios no Reparo do DNA/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioma/complicações , Neoplasias Encefálicas/tratamento farmacológico , Estudos de Coortes , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Distúrbios no Reparo do DNA/etiologia , Dacarbazina/uso terapêutico , Progressão da Doença , Feminino , Glioma/tratamento farmacológico , Humanos , Masculino , Mutação/genética , Receptores Imunológicos/genética , Estatísticas não Paramétricas , Temozolomida , Proteínas Supressoras de Tumor/genética
6.
Science ; 343(6167): 189-193, 2014 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-24336570

RESUMO

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Glioma/patologia , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/genética , Antineoplásicos Alquilantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/genética , DNA Helicases/genética , Análise Mutacional de DNA , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Glioma/genética , Humanos , Mutagênese/efeitos dos fármacos , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Temozolomida , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X
7.
Neuro Oncol ; 16(1): 140-6, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24285547

RESUMO

INTRODUCTION: Mutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. Here, we sought to determine the association between H3F3A mutations and adult thalamic glioma. METHODS: Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes--including cancer-related genes and chromatin-modifier genes--were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome. RESULTS: Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 y; range, 17-46), and 7 were from patients over 50 years of age. The H3F3A K27M mutation was present in 10 of the 11 (91%) younger patients and absent from all 7 older patients. Additionally, H3F3A K27M was not detected in the 2 diffuse astrocytomas. Further sequencing revealed recurrent mutations in TP53, ATRX, NF1, and EGFR. Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. CONCLUSION: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Mutação/genética , Doenças Talâmicas/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilação de DNA , Feminino , Seguimentos , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Taxa de Sobrevida , Doenças Talâmicas/mortalidade , Doenças Talâmicas/patologia , Adulto Jovem
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