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1.
Cell ; 149(5): 994-1007, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22608083

RESUMO

Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.


Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica , Evolução Clonal , Mutação , Algoritmos , Aberrações Cromossômicas , Feminino , Humanos , Mutação Puntual
2.
Cell ; 149(5): 979-93, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22608084

RESUMO

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.


Assuntos
Neoplasias da Mama/genética , Análise Mutacional de DNA , Estudo de Associação Genômica Ampla , Mutação , Desaminase APOBEC-1 , Proteína BRCA2/genética , Citidina Desaminase/metabolismo , Feminino , Genes BRCA1 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
3.
Cell ; 144(1): 27-40, 2011 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-21215367

RESUMO

Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%-3% of all cancers, across many subtypes, and is present in ∼25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer.


Assuntos
Aberrações Cromossômicas , Neoplasias/genética , Neoplasias/patologia , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Coloração Cromossômica , Feminino , Rearranjo Gênico , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Pessoa de Meia-Idade
4.
Nature ; 467(7319): 1109-13, 2010 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-20981101

RESUMO

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.


Assuntos
Instabilidade Genômica/genética , Mutagênese/genética , Metástase Neoplásica/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Ciclo Celular/genética , Linhagem da Célula/genética , Células Clonais/metabolismo , Células Clonais/patologia , Análise Mutacional de DNA , Progressão da Doença , Evolução Molecular , Genes Neoplásicos/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Metástase Neoplásica/patologia , Especificidade de Órgãos , Telômero/genética , Telômero/patologia
5.
Nature ; 463(7278): 184-90, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-20016488

RESUMO

Cancer is driven by mutation. Worldwide, tobacco smoking is the principal lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in frame, and another two lines carrying PVT1-CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.


Assuntos
Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Mutação/genética , Nicotiana/efeitos adversos , Carcinoma de Pequenas Células do Pulmão/etiologia , Carcinoma de Pequenas Células do Pulmão/genética , Fumar/efeitos adversos , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA/efeitos dos fármacos , Variações do Número de Cópias de DNA/genética , Dano ao DNA/genética , DNA Helicases/genética , Análise Mutacional de DNA , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Éxons/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genoma Humano/efeitos dos fármacos , Genoma Humano/genética , Humanos , Mutagênese Insercional/efeitos dos fármacos , Mutagênese Insercional/genética , Mutação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Deleção de Sequência/genética
6.
Nature ; 463(7278): 191-6, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-20016485

RESUMO

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.


Assuntos
Genes Neoplásicos/genética , Genoma Humano/genética , Mutação/genética , Neoplasias/genética , Adulto , Linhagem Celular Tumoral , Dano ao DNA/genética , Análise Mutacional de DNA , Reparo do DNA/genética , Dosagem de Genes/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Melanoma/etiologia , Melanoma/genética , MicroRNAs/genética , Mutagênese Insercional/genética , Neoplasias/etiologia , Polimorfismo de Nucleotídeo Único/genética , Medicina de Precisão , Deleção de Sequência/genética , Raios Ultravioleta
7.
Blood ; 122(22): 3616-27; quiz 3699, 2013 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-24030381

RESUMO

Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.


Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Progressão da Doença , Epistasia Genética , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crônica/genética , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/genética , Oncogenes , Prognóstico , Splicing de RNA/genética , Spliceossomos/genética
8.
Nature ; 462(7276): 1005-10, 2009 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-20033038

RESUMO

Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.


Assuntos
Neoplasias da Mama/genética , Aberrações Cromossômicas , Rearranjo Gênico/genética , Genoma Humano/genética , Linhagem Celular Tumoral , Células Cultivadas , Quebras de DNA , Feminino , Biblioteca Genômica , Humanos , Análise de Sequência de DNA
9.
Blood ; 118(24): 6239-46, 2011 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-21998214

RESUMO

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.


Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/fisiopatologia , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/fisiopatologia , Fosfoproteínas/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Idoso , Alelos , Códon , Análise Mutacional de DNA , Eritroblastos/patologia , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Prognóstico , Fatores de Processamento de RNA , Caracteres Sexuais , Análise de Sobrevida
10.
Genes Chromosomes Cancer ; 49(11): 1062-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20725990

RESUMO

Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors.


Assuntos
Neoplasias da Mama/genética , Rearranjo Gênico , Osteossarcoma/genética , Adulto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia
11.
Nat Med ; 21(7): 751-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26099045

RESUMO

The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células , Células Clonais , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Feminino , Genômica , Humanos , Pessoa de Meia-Idade , Mutação/genética
12.
Genome Biol ; 11(10): R100, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20942901

RESUMO

BACKGROUND: Here we present the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and Brca2-associated hereditary breast cancer, and E-cadherin (Cdh1) mutated lobular breast cancer. RESULTS: We show that although Brca1- and Brca2-deficient mouse mammary tumors have a defect in the homologous recombination pathway, there is no apparent difference in the type or frequency of somatic rearrangements found in these cancers when compared to other mouse mammary cancers, and tumors from all genetic backgrounds showed evidence of microhomology-mediated repair and non-homologous end-joining processes. Importantly, mouse mammary tumors were found to carry fewer structural rearrangements than human mammary cancers and expressed in-frame fusion genes. Like the fusion genes found in human mammary tumors, these were not recurrent. One mouse tumor was found to contain an internal deletion of exons of the Lrp1b gene, which led to a smaller in-frame transcript. We found internal in-frame deletions in the human ortholog of this gene in a significant number (4.2%) of human cancer cell lines. CONCLUSIONS: Paired-end sequencing of mouse mammary tumors revealed that they display significant heterogeneity in their profiles of somatic rearrangement but, importantly, fewer rearrangements than cognate human mammary tumors, probably because these cancers have been induced by strong driver mutations engineered into the mouse genome. Both human and mouse mammary cancers carry expressed fusion genes and conserved homozygous deletions.


Assuntos
Animais Geneticamente Modificados , Neoplasias da Mama/genética , Rearranjo Gênico , Mutação , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Sequência de Bases , Caderinas/metabolismo , Linhagem Celular Tumoral , Feminino , Fusão Gênica , Biblioteca Genômica , Humanos , Camundongos , Receptores de LDL/genética , Deleção de Sequência , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética
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