Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 85
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Clin Cancer Res ; 26(1): 135-146, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481506

RESUMO

PURPOSE: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. EXPERIMENTAL DESIGN: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG). RESULTS: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. CONCLUSIONS: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.See related commentary by Mehla and Singh, p. 6.

2.
J Mol Diagn ; 22(2): 141-146, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837431

RESUMO

Sample tracking and identity are essential when processing multiple samples in parallel. Sequencing applications often involve high sample numbers, and the data are frequently used in a clinical setting. As such, a simple and accurate intrinsic sample tracking process through a sequencing pipeline is essential. Various solutions have been implemented to verify sample identity, including variant detection at the start and end of the pipeline using arrays or genotyping, bioinformatic comparisons, and optical barcoding of samples. None of these approaches are optimal. To establish a more effective approach using genetic barcoding, we developed a panel of unique DNA sequences cloned into a common vector. A unique DNA sequence is added to the sample when it is first received and can be detected by PCR and/or sequencing at any stage of the process. The control sequences are approximately 200 bases long with low identity to any sequence in the National Center for Biotechnology Information nonredundant database (<30 bases) and contain no long homopolymer (>7) stretches. When a spiked next-generation sequencing library is sequenced, sequence reads derived from this control sequence are generated along with the standard sequencing run and are used to confirm sample identity and determine cross-contamination levels. This approach is used in our targeted clinical diagnostic whole-genome and RNA-sequencing pipelines and is an inexpensive, flexible, and platform-agnostic solution.

3.
Cell Rep ; 29(8): 2338-2354.e7, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31708418

RESUMO

Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.

4.
PLoS One ; 14(10): e0224578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31671154

RESUMO

Next generation RNA-sequencing (RNA-seq) is a flexible approach that can be applied to a range of applications including global quantification of transcript expression, the characterization of RNA structure such as splicing patterns and profiling of expressed mutations. Many RNA-seq protocols require up to microgram levels of total RNA input amounts to generate high quality data, and thus remain impractical for the limited starting material amounts typically obtained from rare cell populations, such as those from early developmental stages or from laser micro-dissected clinical samples. Here, we present an assessment of the contemporary ribosomal RNA depletion-based protocols, and identify those that are suitable for inputs as low as 1-10 ng of intact total RNA and 100-500 ng of partially degraded RNA from formalin-fixed paraffin-embedded tissues.

5.
Proc Natl Acad Sci U S A ; 116(38): 19098-19108, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31471491

RESUMO

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole-genome sequencing of 201 samples and RNA sequencing of 118 samples, we show that BTICs and xenografts resemble their parental tumor at the genomic level but differ at the mRNA expression and epigenomic levels, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models. We also found that lack of MGMT expression in pretreated GBM is linked to hypermutation, which in turn contributes to increased genomic heterogeneity and requires new strategies for GBM treatment.

6.
J Pathol ; 249(3): 319-331, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31236944

RESUMO

Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

7.
Microbiol Resour Announc ; 8(24)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196920

RESUMO

Engelmann spruce (Picea engelmannii) is a conifer found primarily on the west coast of North America. Here, we present the complete chloroplast genome sequence of Picea engelmannii genotype Se404-851. This chloroplast sequence will benefit future conifer genomic research and contribute resources to further species conservation efforts.

8.
Microbiol Resour Announc ; 8(23)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171622

RESUMO

Here, we present the complete chloroplast genome sequence of white spruce (Picea glauca, genotype WS77111), a coniferous tree widespread in the boreal forests of North America. This sequence contributes to genomic and phylogenetic analyses of the Picea genus that are part of ongoing research to understand their adaptation to environmental stress.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31160355

RESUMO

Pancreatic neuroendocrine neoplasms (PanNENs) represent a minority of pancreatic neoplasms that exhibit variability in prognosis. Ongoing mutational analyses of PanNENs have found recurrent abnormalities in chromatin remodeling genes (e.g., DAXX and ATRX), and mTOR pathway genes (e.g., TSC2, PTEN PIK3CA, and MEN1), some of which have relevance to patients with related familial syndromes. Most recently, grade 3 PanNENs have been divided into two groups based on differentiation, creating a new group of well-differentiated grade 3 neuroendocrine tumors (PanNETs) that have had a limited whole-genome level characterization to date. In a patient with a metastatic well-differentiated grade 3 PanNET, our study utilized whole-genome sequencing of liver metastases for the comparative analysis and detection of single-nucleotide variants, insertions and deletions, structural variants, and copy-number variants, with their biologic relevance confirmed by RNA sequencing. We found that this tumor most notably exhibited a TSC1-disrupting fusion, showed a novel CHD7-BEND2 fusion, and lacked any somatic variants in ATRX, DAXX, and MEN1.

10.
Clin Cancer Res ; 25(15): 4674-4681, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31068372

RESUMO

PURPOSE: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion-positive pancreatic ductal adenocarcinoma is not fully understood. EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. CONCLUSIONS: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib.See related commentary by Aguirre, p. 4589.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pancreáticas , Feminino , Fusão Gênica , Rearranjo Gênico , Humanos , Neuregulina-1 , Proteínas de Fusão Oncogênica/genética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas p21(ras)
11.
Biotechniques ; 66(2): 85-92, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30744412

RESUMO

The analysis of cell-free circulating tumor DNA (ctDNA) is potentially a less invasive, more dynamic assessment of cancer progression and treatment response than characterizing solid tumor biopsies. Standard isolation methods require separation of plasma by centrifugation, a time-consuming step that complicates automation. To address these limitations, we present an automatable magnetic bead-based ctDNA isolation method that eliminates centrifugation to purify ctDNA directly from peripheral blood (PB). To develop and test our method, ctDNA from cancer patients was purified from PB and plasma. We found that allelic fractions of somatic single-nucleotide variants from target gene capture libraries were comparable, indicating that the PB ctDNA purification method may be a suitable replacement for the plasma-based protocols currently in use.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA Tumoral Circulante/sangue , Ensaios de Triagem em Larga Escala/métodos , Neoplasias/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/isolamento & purificação , Ácidos Nucleicos Livres/isolamento & purificação , DNA Tumoral Circulante/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Neoplasias/genética
12.
Bioinformatics ; 35(3): 515-517, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30016509

RESUMO

Summary: Reliably identifying genomic rearrangements and interpreting their impact is a key step in understanding their role in human cancers and inherited genetic diseases. Many short read algorithmic approaches exist but all have appreciable false negative rates. A common approach is to evaluate the union of multiple tools increasing sensitivity, followed by filtering to retain specificity. Here we describe an application framework for the rapid generation of structural variant consensus, unique in its ability to visualize the genetic impact and context as well as process both genome and transcriptome data. Availability and implementation: http://mavis.bcgsc.ca. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Genômica , Neoplasias/genética , Software , Biologia Computacional , Humanos , Transcriptoma
13.
Nucleic Acids Res ; 47(2): e12, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30418619

RESUMO

Tissues used in pathology laboratories are typically stored in the form of formalin-fixed, paraffin-embedded (FFPE) samples. One important consideration in repurposing FFPE material for next generation sequencing (NGS) analysis is the sequencing artifacts that can arise from the significant damage to nucleic acids due to treatment with formalin, storage at room temperature and extraction. One such class of artifacts consists of chimeric reads that appear to be derived from non-contiguous portions of the genome. Here, we show that a major proportion of such chimeric reads align to both the 'Watson' and 'Crick' strands of the reference genome. We refer to these as strand-split artifact reads (SSARs). This study provides a conceptual framework for the mechanistic basis of the genesis of SSARs and other chimeric artifacts along with supporting experimental evidence, which have led to approaches to reduce the levels of such artifacts. We demonstrate that one of these approaches, involving S1 nuclease-mediated removal of single-stranded fragments and overhangs, also reduces sequence bias, base error rates, and false positive detection of copy number and single nucleotide variants. Finally, we describe an analytical approach for quantifying SSARs from NGS data.


Assuntos
Artefatos , Fixadores , Formaldeído , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA , Animais , Biblioteca Genômica , Genômica , Temperatura Alta , Camundongos Endogâmicos C57BL , Inclusão em Parafina
14.
Nature ; 562(7727): 373-379, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30209392

RESUMO

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.


Assuntos
Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/patologia , Linhagem da Célula/genética , Análise Mutacional de DNA , Feminino , Variação Genética/genética , Genoma Humano/genética , Genômica , Humanos , Imunofenotipagem , Leucemia Aguda Bifenotípica/classificação , Masculino , Modelos Genéticos , Mutação/genética , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Transativadores/genética
16.
Artigo em Inglês | MEDLINE | ID: mdl-29610392

RESUMO

Metastatic adenoid cystic carcinomas (ACCs) can cause significant morbidity and mortality. Because of their slow growth and relative rarity, there is limited evidence for systemic therapy regimens. Recently, molecular profiling studies have begun to reveal the genetic landscape of these poorly understood cancers, and new treatment possibilities are beginning to emerge. The objective is to use whole-genome and transcriptome sequencing and analysis to better understand the genetic alterations underlying the pathology of metastatic and rare ACCs and determine potentially actionable therapeutic targets. We report five cases of metastatic ACC, not originating in the salivary glands, in patients enrolled in the Personalized Oncogenomics (POG) Program at the BC Cancer Agency. Genomic workup included whole-genome and transcriptome sequencing, detailed analysis of tumor alterations, and integration with existing knowledge of drug-target combinations to identify potential therapeutic targets. Analysis reveals low mutational burden in these five ACC cases, and mutation signatures that are commonly observed in multiple cancer types. Notably, the only recurrent structural aberration identified was the well-described MYB-NFIB fusion that was present in four of five cases, and one case exhibited a closely related MYBL1-NFIB fusion. Recurrent mutations were also identified in BAP1 and BCOR, with additional mutations in individual samples affecting NOTCH1 and the epigenetic regulators ARID2, SMARCA2, and SMARCB1. Copy changes were rare, and they included amplification of MYC and homozygous loss of CDKN2A in individual samples. Genomic analysis revealed therapeutic targets in all five cases and served to inform a therapeutic choice in three of the cases to date.


Assuntos
Biomarcadores Tumorais , Carcinoma Adenoide Cístico/genética , Genoma Humano , Genômica , Oncogenes , Adulto , Biomarcadores , Carcinoma Adenoide Cístico/diagnóstico , Carcinoma Adenoide Cístico/mortalidade , Tomada de Decisão Clínica , Feminino , Expressão Gênica , Genômica/métodos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Proteínas de Fusão Oncogênica , Medicina de Precisão/métodos , Prognóstico
17.
Dev Cell ; 44(6): 709-724.e6, 2018 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-29551561

RESUMO

Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases.


Assuntos
Acetiltransferases/metabolismo , Proteína de Ligação a CREB/metabolismo , Proteína de Ligação a CREB/fisiologia , Proteínas Hedgehog/metabolismo , Meduloblastoma/patologia , Mutação , Síndrome de Rubinstein-Taybi/patologia , Adulto , Animais , Proteína de Ligação a CREB/genética , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Feminino , Proteínas Hedgehog/genética , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Camundongos Knockout , Neurônios , Fenótipo , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/metabolismo , Transdução de Sinais
18.
Clin Cancer Res ; 23(24): 7521-7530, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29246904

RESUMO

Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response.Experimental Design: In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI).Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04).Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521-30. ©2017 AACR.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Recombinação Homóloga/genética , Neoplasias de Mama Triplo Negativas/genética , Intervalo Livre de Doença , Feminino , Recombinação Homóloga/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Platina/administração & dosagem , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Sequenciamento Completo do Genoma
19.
Nat Commun ; 8(1): 1433, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127278

RESUMO

Frogs play important ecological roles, and several species are important model organisms for scientific research. The globally distributed Ranidae (true frogs) are the largest frog family, and have substantial evolutionary distance from the model laboratory Xenopus frog species. Unfortunately, there are currently no genomic resources for the former, important group of amphibians. More widely applicable amphibian genomic data is urgently needed as more than two-thirds of known species are currently threatened or are undergoing population declines. We report a 5.8 Gbp (NG50 = 69 kbp) genome assembly of a representative North American bullfrog (Rana [Lithobates] catesbeiana). The genome contains over 22,000 predicted protein-coding genes and 6,223 candidate long noncoding RNAs (lncRNAs). RNA-Seq experiments show thyroid hormone causes widespread transcriptional change among protein-coding and putative lncRNA genes. This initial bullfrog draft genome will serve as a key resource with broad utility including amphibian research, developmental biology, and environmental research.


Assuntos
Genoma , RNA Longo não Codificante/genética , Rana catesbeiana/genética , Animais , Biologia Computacional , Genoma Mitocondrial , Masculino , Anotação de Sequência Molecular , América do Norte , Filogenia , RNA Longo não Codificante/metabolismo , Rana catesbeiana/metabolismo , Hormônios Tireóideos/metabolismo
20.
Nat Genet ; 49(10): 1487-1494, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28825729

RESUMO

We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.


Assuntos
Genes Neoplásicos , Neoplasias Renais/genética , Tumor de Wilms/genética , Aneuploidia , Metilação de DNA , Epigênese Genética , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Conformação Proteica , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA