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2.
Nat Commun ; 10(1): 2891, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253791

RESUMO

Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.


Assuntos
Epigenômica , Regulação Leucêmica da Expressão Gênica/fisiologia , Histonas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Animais , Animais Geneticamente Modificados , Antineoplásicos/farmacologia , Sequência de Bases , Células da Medula Óssea , Diferenciação Celular , Transformação Celular Neoplásica , DNA/genética , Drosophila melanogaster/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Mutação , Neoplasias Experimentais
3.
Gene ; 682: 81-91, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30266503

RESUMO

This study elucidates Y chromosome distribution patterns in the three general provincial populations of historical Tibet, Amdo (n = 88), Dotoe (n = 109) and U-Tsang (n = 153) against the backdrop of 37 Asian reference populations. The central aim of this study is to investigate the genetic affinities of the three historical Tibetan populations among themselves and to neighboring populations. Y-SNP and Y-STR profiles were assessed in these historical populations. Correspondence analyses (CA) were generated with Y-SNP haplogroup data. Y-STR haplotypes were determined and employed to generate multidimensional scaling (MDS) plots based on Rst distances. Frequency contour maps of informative Y haplogroups were constructed to visualize the distributions of specific chromosome types. Network analyses based on Y-STR profiles of individuals under specific Y haplogroups were generated to examine the genetic heterogeneity among populations. Average gene diversity values and other parameters of population genetics interest were estimated to characterize the populations. The Y chromosomal results generated in this study indicate that using two sets of markers (Y-SNP, and Y-STR) the three Tibetan populations are genetically distinct. In addition, U-Tsang displays the highest gene diversity, followed by Amdo and Dotoe. The results of this transcontinental biogeographical investigation also indicate various degrees of paternal genetic affinities among these three Tibetan populations depending on the type of loci (Y-SNP or Y-STR) analyzed. The CA generated with Y-SNP haplogroup data demonstrates that Amdo and U-Tsang are closer to each other than to any neighboring non-Tibetan group. In contrast, the MDS plot based on Y-STR haplotypes displays Rst distances that are much shorter between U-Tsang and its geographic nearby populations of Ladakh, Punjab, Kathmandu and Newar than between it and Amdo. Moreover, although Dotoe is isolated from all other groups using both types of marker systems, it lies nearer to the other Tibetan collections in the Y-SNP CA than in the Y-STR MDS plot. High resolution and shallow evolutionary time frames engendered by Y-STR based analyses may reflect a more recent demographic history than that delineated by the more conserved Y-SNP markers.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Y , Variação Genética , Genética Populacional , Polimorfismo de Nucleotídeo Único , Grupos Étnicos/genética , Feminino , Frequência do Gene , Marcadores Genéticos , Genótipo , Geografia , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Filogenia , Tibet/etnologia
4.
Nat Commun ; 9(1): 4572, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385747

RESUMO

Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin with limited available therapies. Here, we analyze 58 sporadic samples using next generation or targeted sequencing and report somatic, heterozygous, gain-of-function mutations in KRAS, FGFR1, and p.M713V/I-TRPV4 in 72% (42/58) of GCLJ. TRPV4 p.M713V/I mutations are exclusive to central GCLJ and occur at a critical position adjacent to the cation permeable pore of the channel. Expression of TRPV4 mutants in HEK293 cells leads to increased cell death, as well as increased constitutive and stimulated channel activity, both of which can be prevented using TRPV4 antagonists. Furthermore, these mutations induce sustained activation of ERK1/2, indicating that their effects converge with that of KRAS and FGFR1 mutations on the activation of the MAPK pathway in GCLJ. Our data extend the spectrum of TRPV4 channelopathies and provide rationale for the use of TRPV4 and RAS/MAPK antagonists at the bedside in GCLJ.

5.
Nat Genet ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429576

RESUMO

In the version of this article originally published, the main-text sentence "In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor" misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.

6.
Nat Genet ; 50(12): 1650-1657, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374066

RESUMO

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.

8.
Acta Neuropathol Commun ; 5(1): 78, 2017 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-29084603

RESUMO

Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Adulto , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Metilação de DNA , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Adulto Jovem
10.
Nat Genet ; 49(5): 780-788, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28394352

RESUMO

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.


Assuntos
Neoplasias Cerebelares/genética , Regulação Neoplásica da Expressão Gênica , Meduloblastoma/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Análise por Conglomerados , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Humanos , Mutação INDEL , Masculino , Meduloblastoma/patologia , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
Nat Genet ; 49(2): 180-185, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28067913

RESUMO

Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes. histones. We further validate the presence of these alterations in multiple independent HNSCC data sets and show that, along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-negative HNSCCs driven by aberrant H3K36 methylation.


Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA/genética , Neoplasias de Cabeça e Pescoço/genética , Histonas/genética , Carcinogênese/genética , Diferenciação Celular/genética , Epigênese Genética/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Proteínas Nucleares/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
12.
Pediatr Blood Cancer ; 64(2): 275-278, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27718322

RESUMO

A cerebellar pilocytic astrocytoma (PA) in a child recurred first with a PA histology and then with features of a ganglioglioma (GG). Molecular genetic analyses of the tumors confirmed a BRAF V600E mutation in all. They also all harbored a T202M mutation in ERK1, a kinase downstream of BRAF that is implicated in glial versus neuronal differentiation. The GG sample contained several variants that were not present in the PA samples; in particular, it had a truncating mutation in MAP2. These findings not only underscore the role of BRAF as oncogenic driver but also suggest that other genes may influence tumor morphology.


Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/etiologia , Neoplasias Cerebelares/genética , Ganglioglioma/etiologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/complicações , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/patologia , Pré-Escolar , Análise Mutacional de DNA , Feminino , Ganglioglioma/patologia , Humanos , Recidiva Local de Neoplasia , Prognóstico
13.
Leg Med (Tokyo) ; 21: 29-32, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27497330

RESUMO

A total of 223 samples from the general population of Ladakh in Northwestern India were amplified at 17 Y-STR loci using the AmpFlSTR® Yfiler™ system. The DNA profiles generated were employed to generate allelic frequencies, gene diversity, haplotype diversity and discrimination capacity values as well as number of different haplotypes, fraction of unique haplotypes and Rst pair wise genetic distances. Multidimensional Scaling (MDS) and Correspondence Analysis (CA) were performed with the Rst values and allelic frequencies, respectively. The 17-loci discrimination capacity of Ladakh was found to be 0.8093. Eleven out of the 16 loci have diversity values greater than 0.6, and 13 loci possess values greater than 0.5. Ladakh exhibits no significant genetic difference to seven of the 15 reference forensic databases after Bonferroni correction, three of which are located in South Central Asian and four are from the Himalayan region. Rst genetic distance values before and after Bonferroni corrections illustrate the capacity of the Yfiler system to discriminate among Himalayan populations. The intermediate position of the Ladakh population in the MDS and CA plots likely reflects genetic flow and admixture with neighboring populations. In addition, the longitudinal partition of populations in the MDS and CA plots likely reflect human dispersals such as the silk road migrations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Y , Genética Populacional , Repetições de Microssatélites , Genética Forense , Humanos , Índia , Masculino
14.
Oncotarget ; 7(32): 51991-52002, 2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27437771

RESUMO

Extracellular vesicles (EVs) enable the exit of regulatory, mutant and oncogenic macromolecules (proteins, RNA and DNA) from their parental tumor cells and uptake of this material by unrelated cellular populations. Among the resulting biological effects of interest is the notion that cancer-derived EVs may mediate horizontal transformation of normal cells through transfer of mutant genes, including mutant ras. Here, we report that H-ras-mediated transformation of intestinal epithelial cells (IEC-18) results in the emission of exosome-like EVs containing genomic DNA, HRAS oncoprotein and transcript. However, EV-mediated horizontal transformation of non-transformed cells (epithelial, astrocytic, fibroblastic and endothelial) is transient, limited or absent due to barrier mechanisms that curtail the uptake, retention and function of oncogenic H-ras in recipient cells. Thus, epithelial cells and astrocytes are resistant to EV uptake, unless they undergo malignant transformation. In contrast, primary and immortalized fibroblasts are susceptible to the EV uptake, retention of H-ras DNA and phenotypic transformation, but these effects are transient and fail to produce a permanent tumorigenic conversion of these cells in vitro and in vivo, even after several months of observation. Increased exposure to EVs isolated from H-ras-transformed cancer cells, but not to those from their indolent counterparts, triggers demise of recipient fibroblasts. Uptake of H-ras-containing EVs stimulates but fails to transform primary endothelial cells. Thus, we suggest that intercellular transfer of oncogenes exerts regulatory rather than transforming influence on recipient cells, while cancer cells may often act as preferential EV recipients.


Assuntos
Comunicação Celular/fisiologia , Transformação Celular Neoplásica/genética , Vesículas Extracelulares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Xenoenxertos , Humanos , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas p21(ras)/genética
15.
Nat Commun ; 7: 11185, 2016 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-27048880

RESUMO

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.


Assuntos
Neoplasias do Tronco Encefálico/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Histonas/genética , Mutação , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Autopsia , Mapeamento Encefálico , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/metabolismo , Neoplasias do Tronco Encefálico/patologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Cérebro/metabolismo , Cérebro/patologia , Criança , Evolução Clonal , Glioma/metabolismo , Glioma/patologia , Histonas/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Proteína Fosfatase 2C , Transdução de Sinais , Técnicas Estereotáxicas , Fatores de Tempo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
16.
Mamm Genome ; 27(3-4): 122-34, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26951114

RESUMO

Polymorphisms and decreased activity of methylenetetrahydrofolate reductase (MTHFR) are linked to disease, including cancer. However, epigenetic regulation has not been thoroughly studied. Our goal was to generate DNA methylation profiles of murine/human MTHFR gene regions and examine methylation in brain and liver tumors. Pyrosequencing in four murine tissues revealed minimal DNA methylation in the CpG island. Higher methylation was seen in liver or intestine in the CpG island shore 5' to the upstream translational start site or in another region 3' to the downstream start site. In the latter region, there was negative correlation between expression and methylation. Three orthologous regions were investigated in human MTHFR, as well as a fourth region between the two translation start sites. We found significantly increased methylation in three regions (not the CpG island) in pediatric astrocytomas compared with control brain, with decreased expression in tumors. Methylation in hepatic carcinomas was also increased in the three regions compared with normal liver, but the difference was significant for only one CpG. This work, the first overview of the Mthfr/MTHFR epigenetic landscape, suggests regulation through methylation in some regions, demonstrates increased methylation/decreased expression in pediatric astrocytomas, and should serve as a resource for future epigenetic studies.


Assuntos
Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica , Metilação de DNA , Dieta , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Animais , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Ilhas de CpG , Modelos Animais de Doenças , Epigênese Genética , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Baço/metabolismo
17.
Lancet Oncol ; 17(4): 484-495, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26976201

RESUMO

BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.


Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/cirurgia , Meduloblastoma/classificação , Meduloblastoma/cirurgia , Prognóstico , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Canadá , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Estudos Retrospectivos
18.
Acta Neuropathol ; 131(6): 847-63, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26920151

RESUMO

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.


Assuntos
Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA/genética , Glioma/genética , Mutação/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Adulto , Feminino , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteínas Proto-Oncogênicas B-raf/genética , Adulto Jovem
19.
Oncotarget ; 7(2): 1732-40, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26646792

RESUMO

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy diagnosed in women under age 40. We and others recently determined that germline and/or somatic deleterious mutations in SMARCA4 characterize SCCOHT. Alterations in this gene, or the related SWI/SNF chromatin remodeling gene SMARCB1, have been previously reported in atypical teratoid/rhabdoid tumors (ATRTs) and malignant rhabdoid tumors (MRTs). To further describe the somatic landscape of SCCOHT, we performed whole exome sequencing on 14 tumors and their matched normal tissues and compared their genomic alterations with those in ATRT and ovarian high grade serous carcinoma (HGSC). We confirmed that SMARCA4 is the only recurrently mutated gene in SCCOHT, and show that recurrent allelic imbalance is observed exclusively on chromosome 19p, where SMARCA4 resides. By comparing genomic alterations between SCCOHT, ATRT and HGSC, we demonstrate that SCCOHTs, like ATRTs, have a remarkably simple genome and harbor significantly fewer somatic protein-coding mutations and chromosomal alterations than HGSC. Furthermore, a comparison of global DNA methylation profiles of 45 SCCOHTs, 65 ATRTs, and 92 HGSCs demonstrates a strong epigenetic correlation between SCCOHT and ATRT. Our results further confirm that the genomic and epigenomic signatures of SCCOHT are more similar to those of ATRT than HGSC, supporting our previous hypothesis that SCCOHT is a rhabdoid tumor and should be renamed MRT of the ovary. Furthermore, we conclude that SMARCA4 inactivation is the main cause of SCCOHT, and that new distinct therapeutic approaches should be developed to specifically target this devastating tumor.


Assuntos
Carcinoma de Células Pequenas/genética , Predisposição Genética para Doença/genética , Hipercalcemia/genética , Neoplasias Ovarianas/genética , Tumor Rabdoide/genética , Teratoma/genética , Cistadenocarcinoma Seroso/genética , DNA Helicases/genética , Metilação de DNA , Epigenômica/métodos , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Mutação , Proteínas Nucleares/genética , Análise de Sequência de DNA/métodos , Fatores de Transcrição/genética
20.
Eur J Hum Genet ; 24(3): 442-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25966630

RESUMO

Owing to its geographic location near the longitudinal center of Asia, Ladakh, the land of high passes, has witnessed numerous demographic movements during the past millenniums of occupation. In an effort to view Ladakh's multicultural history from a paternal genetic perspective, we performed a high-resolution Y-chromosomal survey of Ladakh, within the context of Y haplogroup and haplotype distributions of 41 Asian reference populations. The results of this investigation highlight the rich ethnic and genetic diversity of Ladkah which includes genetic contributions from disparate regions of the continent including, West, East, South and Central Asia. The phylogenetic signals from Ladakh are consistent with the Indo-Aryans' occupation during the Neolithic age and its historic connection with Tibet, as well as the East-West gene flow associated with the Silk Road.


Assuntos
Heterogeneidade Genética , Migração Humana , Cromossomos Humanos Y/genética , Variação Genética , Genética Populacional , Haplótipos/genética , Humanos , Índia , Filogeografia , Fatores de Tempo
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