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1.
Cell ; 161(4): 933-45, 2015 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-25957691

RESUMEN

In Rspondin-based 3D cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. We report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely recapitulate several properties of the original tumor. The spectrum of genetic changes within the "living biobank" agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell-line- and xenograft-based drug studies, and allow personalized therapy design. PAPERCLIP.


Asunto(s)
Bancos de Muestras Biológicas , Neoplasias Colorrectales/patología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Organoides , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas de Unión al ADN/metabolismo , Humanos , Proteínas Oncogénicas/metabolismo , Técnicas de Cultivo de Órganos , Organoides/efectos de los fármacos , Medicina de Precisión , Ubiquitina-Proteína Ligasas
2.
Cell ; 156(6): 1298-1311, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24630729

RESUMEN

Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs.


Asunto(s)
Carcinogénesis , Modelos Animales de Enfermedad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Animales , Humanos , Neoplasias Hepáticas/secundario , Metástasis Linfática , Ratones , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Carcinoma Pulmonar de Células Pequeñas/secundario
3.
Cell ; 152(4): 714-26, 2013 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-23415222

RESUMEN

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Mutación , Algoritmos , Animales , Linfocitos B/metabolismo , Variaciones en el Número de Copia de ADN , Estudio de Asociación del Genoma Completo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Ploidias
4.
Cell ; 153(3): 666-77, 2013 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-23622249

RESUMEN

The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy," frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.


Asunto(s)
Aberraciones Cromosómicas , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Neoplasias de la Próstata/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Estudios de Cohortes , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias de la Próstata/patología
5.
Immunity ; 46(2): 197-204, 2017 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-28228279

RESUMEN

Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p = 0.039). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.


Asunto(s)
Resistencia a Antineoplásicos/genética , Leiomiosarcoma/patología , Fosfohidrolasa PTEN/genética , Neoplasias Uterinas/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Análisis Mutacional de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/genética , Persona de Mediana Edad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Transcriptoma , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética
6.
Bioinformatics ; 38(8): 2096-2101, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35176131

RESUMEN

MOTIVATION: Cross-sectional analyses of primary cancer genomes have identified regions of recurrent somatic copy-number alteration, many of which result from positive selection during cancer formation and contain driver genes. However, no effective approach exists for identifying genomic loci under significantly different degrees of selection in cancers of different subtypes, anatomic sites or disease stages. RESULTS: CNGPLD is a new tool for performing case-control somatic copy-number analysis that facilitates the discovery of differentially amplified or deleted copy-number aberrations in a case group of cancer compared with a control group of cancer. This tool uses a Gaussian process statistical framework in order to account for the covariance structure of copy-number data along genomic coordinates and to control the false discovery rate at the region level. AVAILABILITY AND IMPLEMENTATION: CNGPLD is freely available at https://bitbucket.org/djhshih/cngpld as an R package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Genoma , Neoplasias , Humanos , Estudios Transversales , Genómica , Variaciones en el Número de Copia de ADN , Neoplasias/genética , Estudios de Casos y Controles , Programas Informáticos
7.
Bioinformatics ; 38(20): 4677-4686, 2022 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-36040167

RESUMEN

MOTIVATION: Somatic copy-number alterations (SCNAs) play an important role in cancer development. Systematic noise in sequencing and array data present a significant challenge to the inference of SCNAs for cancer genome analyses. As part of The Cancer Genome Atlas, the Broad Institute Genome Characterization Center developed the Tangent normalization method to generate copy-number profiles using data from single-nucleotide polymorphism (SNP) arrays and whole-exome sequencing (WES) technologies for over 10 000 pairs of tumors and matched normal samples. Here, we describe the Tangent method, which uses a unique linear combination of normal samples as a reference for each tumor sample, to subtract systematic errors that vary across samples. We also describe a modification of Tangent, called Pseudo-Tangent, which enables denoising through comparisons between tumor profiles when few normal samples are available. RESULTS: Tangent normalization substantially increases signal-to-noise ratios (SNRs) compared to conventional normalization methods in both SNP array and WES analyses. Tangent and Pseudo-Tangent normalizations improve the SNR by reducing noise with minimal effect on signal and exceed the contribution of other steps in the analysis such as choice of segmentation algorithm. Tangent and Pseudo-Tangent are broadly applicable and enable more accurate inference of SCNAs from DNA sequencing and array data. AVAILABILITY AND IMPLEMENTATION: Tangent is available at https://github.com/broadinstitute/tangent and as a Docker image (https://hub.docker.com/r/broadinstitute/tangent). Tangent is also the normalization method for the copy-number pipeline in Genome Analysis Toolkit 4 (GATK4). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Neoplasias , Programas Informáticos , Humanos , Algoritmos , Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética
8.
Nature ; 540(7631): 114-118, 2016 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-27905446

RESUMEN

Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.


Asunto(s)
Resistencia a Antineoplásicos , Genoma Humano/genética , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/genética , Apoptosis , Progresión de la Enfermedad , Evolución Molecular , Exoma/genética , Genómica , Humanos , Pérdida de Heterocigocidad , Masculino , Mitocondrias/metabolismo , Mutación , Proteína Homeótica Nanog/deficiencia , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Factor 3 de Transcripción de Unión a Octámeros/deficiencia , Filogenia , Proteínas Proto-Oncogénicas p21(ras)/genética , Teratoma/genética , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patología , Transcriptoma/genética , Proteína p53 Supresora de Tumor/genética
9.
Nature ; 526(7574): 525-30, 2015 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-26466571

RESUMEN

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.


Asunto(s)
Progresión de la Enfermedad , Evolución Molecular , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Transformación Celular Neoplásica/genética , Células Clonales/metabolismo , Células Clonales/patología , Variaciones en el Número de Copia de ADN/genética , Exoma/genética , Genes myc/genética , Humanos , Factor de Transcripción Ikaros/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/terapia , Sistema de Señalización de MAP Quinasas/genética , Pronóstico , Procesamiento Postranscripcional del ARN/genética , Transporte de ARN/genética , Proteínas Ribosómicas/genética , Resultado del Tratamiento
10.
Nature ; 506(7488): 371-5, 2014 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-24390348

RESUMEN

Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.


Asunto(s)
Genoma Humano/genética , Mutación/genética , Neoplasias del Cuello Uterino/genética , Adenocarcinoma/genética , Adenocarcinoma/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Proteína p300 Asociada a E1A/genética , Exoma/genética , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genómica , Antígenos HLA-B/genética , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Factor 2 Relacionado con NF-E2/genética , Papillomaviridae/genética , Papillomaviridae/fisiología , Infecciones por Papillomavirus/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , Receptor ErbB-2/genética , Factores de Transcripción/genética , Transcriptoma/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Neoplasias del Cuello Uterino/virología , Integración Viral/genética
11.
Gastroenterology ; 155(1): 156-167, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29608884

RESUMEN

BACKGROUND & AIMS: Barrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress. METHODS: We performed a retrospective case-control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non-progressors. RESULTS: TP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case-control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes-the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy). CONCLUSIONS: In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.


Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Neoplasias Esofágicas/genética , Lesiones Precancerosas/genética , Proteína p53 Supresora de Tumor/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/patología , Biopsia , Estudios de Casos y Controles , Progresión de la Enfermedad , Neoplasias Esofágicas/patología , Esofagoscopía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Lesiones Precancerosas/patología , Pronóstico , Estudios Retrospectivos
12.
Nature ; 499(7457): 214-218, 2013 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-23770567

RESUMEN

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.


Asunto(s)
Heterogeneidad Genética , Mutación/genética , Neoplasias/genética , Oncogenes/genética , Artefactos , Momento de Replicación del ADN , Exoma/genética , Reacciones Falso Positivas , Expresión Génica , Genoma Humano/genética , Humanos , Neoplasias Pulmonares/genética , Tasa de Mutación , Neoplasias/clasificación , Neoplasias/patología , Neoplasias de Células Escamosas/genética , Reproducibilidad de los Resultados , Tamaño de la Muestra
13.
Acta Neuropathol ; 136(5): 779-792, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30123936

RESUMEN

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.


Asunto(s)
Distrofina/genética , Eliminación de Gen , Neoplasias Meníngeas/genética , Meningioma/genética , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral/patología , Línea Celular Tumoral/ultraestructura , Estudios de Cohortes , Progresión de la Enfermedad , Distrofina/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Meningioma/diagnóstico por imagen , Meningioma/patología , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , ARN Mensajero/metabolismo , Cromatina Sexual/genética , Telomerasa/genética , Telomerasa/metabolismo , Secuenciación del Exoma
14.
Nature ; 488(7409): 106-10, 2012 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-22820256

RESUMEN

Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, ß-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic ß-catenin signalling in medulloblastoma.


Asunto(s)
Neoplasias Cerebelosas/genética , Exoma/genética , Genoma Humano/genética , Meduloblastoma/genética , Mutación/genética , Neoplasias Cerebelosas/clasificación , Niño , ARN Helicasas DEAD-box/química , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , ADN Helicasas/química , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Proteínas Hedgehog/metabolismo , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/genética , Meduloblastoma/clasificación , Modelos Moleculares , Proteínas de Neoplasias/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Receptores Patched , Receptor Patched-1 , Regiones Promotoras Genéticas/genética , Estructura Terciaria de Proteína/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Superficie Celular/genética , Proteínas Represoras/genética , Transducción de Señal , Factores de Transcripción TCF/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
15.
Nature ; 485(7399): 502-6, 2012 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-22622578

RESUMEN

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.


Asunto(s)
Genoma Humano/genética , Factores de Intercambio de Guanina Nucleótido/genética , Melanoma/genética , Mutación/genética , Luz Solar/efectos adversos , Puntos de Rotura del Cromosoma/efectos de la radiación , Daño del ADN , Análisis Mutacional de ADN , Regulación Neoplásica de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Melanocitos/metabolismo , Melanocitos/patología , Melanoma/patología , Mutagénesis/efectos de la radiación , Mutación/efectos de la radiación , Oncogenes/genética , Rayos Ultravioleta/efectos adversos
16.
Nature ; 486(7403): 405-9, 2012 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-22722202

RESUMEN

Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.


Asunto(s)
Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Mutación/genética , Translocación Genética/genética , Algoritmos , Neoplasias de la Mama/patología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Análisis Mutacional de ADN , Exoma/genética , Femenino , Fusión Génica/genética , Humanos , Proteínas de la Membrana/genética , México , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vietnam
17.
N Engl J Med ; 371(15): 1426-33, 2014 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-25295501

RESUMEN

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.


Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/genética , Neoplasias de la Tiroides/terapia , Proteínas Supresoras de Tumor/genética , Terapia Combinada , Everolimus , Femenino , Humanos , Metástasis Linfática/patología , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/patología , Conformación Proteica , Radiografía , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/química , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Proteína 2 del Complejo de la Esclerosis Tuberosa
18.
Nature ; 470(7333): 214-20, 2011 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-21307934

RESUMEN

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.


Asunto(s)
Genoma Humano/genética , Neoplasias de la Próstata/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras/genética , Estudios de Casos y Controles , Moléculas de Adhesión Celular/genética , Cromatina/genética , Cromatina/metabolismo , Aberraciones Cromosómicas , Puntos de Rotura del Cromosoma , Epigénesis Genética/genética , Regulación Neoplásica de la Expresión Génica , Guanilato-Quinasas , Humanos , Masculino , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Recombinación Genética/genética , Transducción de Señal/genética , Transcripción Genética
19.
Proc Natl Acad Sci U S A ; 111(51): E5564-73, 2014 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-25512523

RESUMEN

Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.


Asunto(s)
Neoplasias Óseas/metabolismo , Genoma Humano , Osteosarcoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Línea Celular Tumoral , Proliferación Celular , Heterogeneidad Genética , Mutación de Línea Germinal , Humanos , Osteosarcoma/genética , Osteosarcoma/patología , Proteína p53 Supresora de Tumor/genética
20.
Genome Res ; 23(2): 228-35, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23124520

RESUMEN

Whole-genome sequencing using massively parallel sequencing technologies enables accurate detection of somatic rearrangements in cancer. Pinpointing large numbers of rearrangement breakpoints to base-pair resolution allows analysis of rearrangement microhomology and genomic location for every sample. Here we analyze 95 tumor genome sequences from breast, head and neck, colorectal, and prostate carcinomas, and from melanoma, multiple myeloma, and chronic lymphocytic leukemia. We discover three genomic factors that are significantly correlated with the distribution of rearrangements: replication time, transcription rate, and GC content. The correlation is complex, and different patterns are observed between tumor types, within tumor types, and even between different types of rearrangements. Mutations in the APC gene correlate with and, hence, potentially contribute to DNA breakage in late-replicating, low %GC, untranscribed regions of the genome. We show that somatic rearrangements display less microhomology than germline rearrangements, and that breakpoint loci are correlated with local hypermutability with a particular enrichment for transversions.


Asunto(s)
Rotura Cromosómica , Mutación , Neoplasias/genética , Recombinación Genética , Composición de Base , Puntos de Rotura del Cromosoma , Biología Computacional/métodos , Replicación del ADN , Humanos , Tasa de Mutación , Transcripción Genética
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