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1.
Nat Commun ; 10(1): 4717, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624251

RESUMO

Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis.

2.
Stem Cells ; 37(5): 609-622, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30681766

RESUMO

Death of photoreceptors is a common cause of age-related and inherited retinal dystrophies, and thus their replenishment from renewable stem cell sources is a highly desirable therapeutic goal. Human pluripotent stem cells provide a useful cell source in view of their limitless self-renewal capacity and potential to not only differentiate into cells of the retina but also self-organize into tissue with structure akin to the human retina as part of three-dimensional retinal organoids. Photoreceptor precursors have been isolated from differentiating human pluripotent stem cells through application of cell surface markers or fluorescent reporter approaches and shown to have a similar transcriptome to fetal photoreceptors. In this study, we investigated the transcriptional profile of CRX-expressing photoreceptor precursors derived from human pluripotent stem cells and their engraftment capacity in an animal model of retinitis pigmentosa (Pde6brd1), which is characterized by rapid photoreceptor degeneration. Single cell RNA-Seq analysis revealed the presence of a dominant cell cluster comprising 72% of the cells, which displayed the hallmarks of early cone photoreceptor expression. When transplanted subretinally into the Pde6brd1 mice, the CRX+ cells settled next to the inner nuclear layer and made connections with the inner neurons of the host retina, and approximately one-third of them expressed the pan cone marker, Arrestin 3, indicating further maturation upon integration into the host retina. Together, our data provide valuable molecular insights into the transcriptional profile of human pluripotent stem cells-derived CRX+ photoreceptor precursors and indicate their usefulness as a source of transplantable cone photoreceptors. Stem Cells 2019;37:609-622.

3.
Stem Cells ; 37(5): 593-598, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30548510

RESUMO

The rapid improvements in single cell sequencing technologies and analyses afford greater scope for dissecting organoid cultures composed of multiple cell types and create an opportunity to interrogate these models to understand tissue biology, cellular behavior and interactions. To this end, retinal organoids generated from human embryonic stem cells (hESCs) were analyzed by single cell RNA-sequencing (scRNA-Seq) at three time points of differentiation. Combinatorial data from all time points revealed the presence of nine clusters, five of which corresponded to key retinal cell types: retinal pigment epithelium (RPE), retinal ganglion cells (RGCs), cone and rod photoreceptors, and Müller glia. The remaining four clusters expressed genes typical of mitotic cells, extracellular matrix components and those involved in homeostasis. The cell clustering analysis revealed the decreasing presence of mitotic cells and RGCs, formation of a distinct RPE cluster, the emergence of cone and rod photoreceptors from photoreceptor precursors, and an increasing number of Müller glia cells over time. Pseudo-time analysis resembled the order of cell birth during retinal development, with the mitotic cluster commencing the trajectory and the large majority of Müller glia completing the time line. Together, these data demonstrate the feasibility and potential of scRNA-Seq to dissect the inherent complexity of retinal organoids and the orderly birth of key retinal cell types. Stem Cells 2019;37:593-598.

4.
Nat Cell Biol ; 20(8): 991, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29674682

RESUMO

In the version of this Letter originally published, an author error led to the affiliations for Brendan Payne, Jonathan Coxhead and Gavin Hudson being incorrect. The correct affiliations are: Brendan Payne: 3Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. 6Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK; this is a new affiliation 6 and subsequent existing affiliations have been renumbered. Jonathan Coxhead: 11Genomic Core Facility, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; this is a new affiliation 11 and subsequent existing affiliations have been renumbered. Gavin Hudson: 3Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. In addition, in Fig. 2d, the numbers on the x-axis of the left plot were incorrectly labelled as negative; they should have been positive. These errors have now been corrected in all online versions of the Letter.

5.
Nat Cell Biol ; 20(2): 144-151, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29335530

RESUMO

Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear1,2. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.

7.
Acta Neuropathol Commun ; 5(1): 13, 2017 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-28153046

RESUMO

Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels. To address these issues we studied 1363 post mortem human brains with a histopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), Frontotemporal dementia - Amyotrophic Lateral Sclerosis (FTD-ALS), Creutzfeldt Jacob disease (CJD), and healthy controls. We obtained high-depth whole mitochondrial genome sequences using off target reads from whole exome sequencing to determine the association of mtDNA variation with the development and progression of disease, and to better understand the development of mtDNA mutations and copy number in the aging brain. With this approach, we found a surprisingly high frequency of heteroplasmic mtDNA variants in 32.3% of subjects. However, we found no evidence of an association between rare inherited variants of mtDNA or mtDNA heteroplasmy and disease. In contrast, we observed a reduction in the amount of mtDNA copy in both AD and CJD. Based on these findings, single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative diseases, but mtDNA levels merit further investigation.


Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , Encéfalo/metabolismo , Variações do Número de Cópias de DNA , DNA Mitocondrial , Mutação Puntual , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Encéfalo/patologia , Encefalopatias/patologia , Estudos de Coortes , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
10.
Neurobiol Aging ; 38: 217.e1-217.e6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26639157

RESUMO

There is a growing body of evidence linking mitochondrial dysfunction, mediated either through inherited mitochondrial DNA (mtDNA) variation or mitochondrial proteomic deficit, to Parkinson's disease (PD). Yet, despite this, the role of somatic mtDNA point mutations and specifically point-mutational burden in PD is poorly understood. Here, we take advantage of recent technical and methodological advances to examine the role of age-related and acquired mtDNA mutation in the largest study of mtDNA in postmortem PD tissue to date. Our data show that PD patients suffer an increase in mtDNA mutational burden in, but no limited to, the substantia nigra pars compacta when compared to matched controls. This mutational burden appears increased in genes encoding cytochrome c oxidase, supportive of previous protein studies of mitochondrial dysfunction in PD. Accepting experimental limitations, our study confirms the important role of age-related mtDNA point mutation in the etiology of PD, moreover, by analyzing 2 distinct brain regions, we are able to show that PD patient brains are more vulnerable to mtDNA mutation overall.


Assuntos
DNA Mitocondrial/genética , Estudos de Associação Genética , Doença de Parkinson/genética , Mutação Puntual/genética , Estudos de Coortes , Complexo IV da Cadeia de Transporte de Elétrons/genética , Humanos
11.
PLoS Genet ; 11(5): e1005040, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25973765

RESUMO

Recent reports have questioned the accepted dogma that mammalian mitochondrial DNA (mtDNA) is strictly maternally inherited. In humans, the argument hinges on detecting a signature of inter-molecular recombination in mtDNA sequences sampled at the population level, inferring a paternal source for the mixed haplotypes. However, interpreting these data is fraught with difficulty, and direct experimental evidence is lacking. Using extreme-high depth mtDNA re-sequencing up to ~1.2 million-fold coverage, we find no evidence that paternal mtDNA haplotypes are transmitted to offspring in humans, thus excluding a simple dilution mechanism for uniparental transmission of mtDNA present in all healthy individuals. Our findings indicate that an active mechanism eliminates paternal mtDNA which likely acts at the molecular level.


Assuntos
DNA Mitocondrial/isolamento & purificação , Padrões de Herança , Análise de Sequência de DNA , Biologia Computacional , DNA Mitocondrial/genética , Feminino , Frequência do Gene , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Oócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Espermatozoides/metabolismo
12.
Methods Mol Biol ; 1264: 59-66, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25631003

RESUMO

Detecting and quantifying low-level variants in mitochondrial DNA (mtDNA) by deep resequencing can lead to important insights into the biology of mtDNA in health and disease. Massively parallel ("next-generation") sequencing is an attractive tool owing to the great depth and breadth of coverage. However, there are several important challenges to be considered when using this method, in particular: the avoidance of false discovery due to the unintended amplification of nuclear pseudogenes and the approach to delineating signal from noise at very great depths of coverage. Here we present methods for whole mtDNA genome deep sequencing (Illumina MiSeq) and short amplicon deep sequencing (Roche 454 GS-FLX).


Assuntos
DNA Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala , DNA Mitocondrial/química , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA/métodos
13.
Ann Neurol ; 76(1): 66-81, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24841123

RESUMO

OBJECTIVE: Polymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using postmortem tissue from a large number of patients. METHODS: Clinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls was studied employing a combination of histopathology, immunohistochemistry, and molecular studies of microdissected neurons. RESULTS: The primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I-deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and that showed massive neuronal loss. INTERPRETATION: POLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to 2 distinct but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears to be related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy.


Assuntos
DNA Polimerase Dirigida por DNA/efeitos adversos , DNA Polimerase Dirigida por DNA/genética , Degeneração Neural/enzimologia , Degeneração Neural/patologia , Adolescente , Adulto , Cerebelo/enzimologia , Cerebelo/patologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Criança , Polimerase do DNA Mitocondrial , DNA Mitocondrial/genética , Progressão da Doença , Humanos , Lactente , Pessoa de Meia-Idade , Encefalomiopatias Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/patologia , Mutação/genética , Substância Negra/enzimologia , Substância Negra/patologia , Adulto Jovem
14.
Acta Neuropathol Commun ; 1: 35, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-24252690

RESUMO

BACKGROUND: Medulloblastomas, the most frequent malignant brain tumours affecting children, comprise at least 4 distinct clinicogenetic subgroups. Aberrant sonic hedgehog (SHH) signalling is observed in approximately 25% of tumours and defines one subgroup. Although alterations in SHH pathway genes (e.g. PTCH1, SUFU) are observed in many of these tumours, high throughput genomic analyses have identified few other recurring mutations. Here, we have mutagenised the Ptch+/- murine tumour model using the Sleeping Beauty transposon system to identify additional genes and pathways involved in SHH subgroup medulloblastoma development. RESULTS: Mutagenesis significantly increased medulloblastoma frequency and identified 17 candidate cancer genes, including orthologs of genes somatically mutated (PTEN, CREBBP) or associated with poor outcome (PTEN, MYT1L) in the human disease. Strikingly, these candidate genes were enriched for transcription factors (p=2x10-5), the majority of which (6/7; Crebbp, Myt1L, Nfia, Nfib, Tead1 and Tgif2) were linked within a single regulatory network enriched for genes associated with a differentiated neuronal phenotype. Furthermore, activity of this network varied significantly between the human subgroups, was associated with metastatic disease, and predicted poor survival specifically within the SHH subgroup of tumours. Igf2, previously implicated in medulloblastoma, was the most differentially expressed gene in murine tumours with network perturbation, and network activity in both mouse and human tumours was characterised by enrichment for multiple gene-sets indicating increased cell proliferation, IGF signalling, MYC target upregulation, and decreased neuronal differentiation. CONCLUSIONS: Collectively, our data support a model of medulloblastoma development in SB-mutagenised Ptch+/- mice which involves disruption of a novel transcription factor network leading to Igf2 upregulation, proliferation of GNPs, and tumour formation. Moreover, our results identify rational therapeutic targets for SHH subgroup tumours, alongside prognostic biomarkers for the identification of poor-risk SHH patients.


Assuntos
Meduloblastoma/genética , Meduloblastoma/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Cerebelo/metabolismo , Cerebelo/patologia , Progressão da Doença , Expressão Gênica , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo
15.
Hum Mol Genet ; 22(2): 384-90, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23077218

RESUMO

Mammalian cells contain thousands of copies of mitochondrial DNA (mtDNA). At birth, these are thought to be identical in most humans. Here, we use long read length ultra-deep resequencing-by-synthesis to interrogate regions of the mtDNA genome from related and unrelated individuals at unprecedented resolution. We show that very low-level heteroplasmic variance is present in all tested healthy individuals, and is likely to be due to both inherited and somatic single base substitutions. Using this approach, we demonstrate an increase in mtDNA mutations in the skeletal muscle of patients with a proofreading-deficient mtDNA polymerase γ due to POLG mutations. In contrast, we show that OPA1 mutations, which indirectly affect mtDNA maintenance, do not increase point mutation load. The demonstration of universal mtDNA heteroplasmy has fundamental implications for our understanding of mtDNA inheritance and evolution. Ostensibly de novo somatic mtDNA mutations, seen in mtDNA maintenance disorders and neurodegenerative disease and aging, will partly be due to the clonal expansion of low-level inherited variants.


Assuntos
DNA Mitocondrial/genética , Variação Genética , Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Padrões de Herança , Músculo Esquelético
16.
Genome Res ; 21(11): 1788-99, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21948523

RESUMO

In silico analyses have established that transcripts from some genes can be processed into RNAs with rearranged exon order relative to genomic structure (post-transcriptional exon shuffling, or PTES). Although known to contribute to transcriptome diversity in some species, to date the structure, distribution, abundance, and functional significance of human PTES transcripts remains largely unknown. Here, using high-throughput transcriptome sequencing, we identify 205 putative human PTES products from 176 genes. We validate 72 out of 112 products analyzed using RT-PCR, and identify additional PTES products structurally related to 61% of validated targets. Sequencing of these additional products reveals GT-AG dinucleotides at >95% of the splice junctions, confirming that they are processed by the spliceosome. We show that most PTES transcripts are expressed in a wide variety of human tissues, that they can be polyadenylated, and that some are conserved in mouse. We also show that they can extend into 5' and 3' UTRs, consistent with formation via trans-splicing of independent pre-mRNA molecules. Finally, we use real-time PCR to compare the abundance of PTES exon junctions relative to canonical exon junctions within the transcripts from seven genes. PTES exon junctions are present at <0.01% to >90% of the levels of canonical junctions, with transcripts from MAN1A2, PHC3, TLE4, and CDK13 exhibiting the highest levels. This is the first systematic experimental analysis of PTES in human, and it suggests both that the phenomenon is much more widespread than previously thought and that some PTES transcripts could be functional.


Assuntos
Evolução Molecular , Éxons , Processamento Pós-Transcricional do RNA , Animais , Sequência de Bases , Embaralhamento de DNA , Regulação da Expressão Gênica , Rearranjo Gênico , Humanos , Camundongos , Dados de Sequência Molecular , Estrutura Molecular , Precursores de RNA/metabolismo , Sítios de Splice de RNA , Processamento de RNA , RNA Mensageiro/metabolismo , Transcriptoma , Regiões não Traduzidas/genética
17.
Nutr Cancer ; 62(1): 105-15, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20043265

RESUMO

The aim of this study was to investigate the differential antineoplastic effects of butyrate in cells with and without a functional mismatch repair and to determine the molecular mechanisms underlying these effects. SW48 colon cancer cells in which the MLH1 gene is silenced by promoter hypermethylation and demethylated SW48 cells in which the MLH1 gene is reexpressed were treated with butyrate (0-5mM) for 8 days and the effects on cell number, MLH1 gene promoter methylation, and expression of two cell cycle regulatory genes, CDK4 and GADD45A, were assessed. Butyrate suppressed viable cell number (P < 0.001) and reduced MLH1 promoter methylation (P < 0.05) in SW48 cells. However, in demethylated SW48 cells, butyrate caused an increase in viable cells (P < 0.05) and promoter methylation (P < 0.05). CDK4 expression was downregulated by butyrate exposure, but the effect was significantly greater for demethylated SW48 cells (P = 0.025). Butyrate treatment caused upregulation of GADD45A expression in SW48 cells but downregulation of GADD45A expression in demethylated SW48 cells (P = 0.045). This study supports the hypothesis that butyrate has more potent antineoplastic effects on colon cancer cells with MLH1 dysfunction. Differential expression of key cell cycle regulatory genes may explain some of the molecular mechanisms underlying these effects.


Assuntos
Antineoplásicos/farmacologia , Butiratos/farmacologia , Reparo de Erro de Pareamento de DNA/genética , Reparo de Erro de Pareamento de DNA/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Neoplasias do Colo , Quinase 4 Dependente de Ciclina/genética , Metilação de DNA/genética , Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Mutação em Linhagem Germinativa , Humanos , Proteína 1 Homóloga a MutL , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
18.
Proc Nutr Soc ; 62(1): 107-15, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12740065

RESUMO

Epidemiological evidence suggests that a high intake of resistant starch and NSP protects against colo-rectal cancer. The mechanisms underlying this protection are thought to be mediated by the short-chain fatty acid butyrate, which is present in the colonic lumen in millimolar concentrations as a result of bacterial fermentation of carbohydrates that have resisted digestion in the small intestine. In vitro studies have shown that butyrate displays a host of chemo-preventative properties including increased apoptosis, reduced proliferation, down regulation of angiogenesis, enhanced immunosurveillance and anti-inflammatory effects in colo-rectal cancer cell lines. However, the molecular mechanisms underlying the apparent chemo-preventative actions of butyrate are largely unknown. The evidence supporting the role of butyrate as an anti-cancer agent is reviewed, with particular emphasis on those studies that have attempted to elucidate the mechanism of action of butyrate. Our understanding of the mechanistic action of butyrate and its role in cancer prevention is likely to advance considerably in this post-genomic era with the application of genomic and proteomic technologies. Studies are described that have used gene array and proteomic techniques to investigate the response of colo-rectal cancer cells to butyrate. These pioneering studies illustrate the potential of these technologies to help characterise the molecular responses of the cancer cell to butyrate, and to define the role of butyrate (and other nutrients) in the prevention of colo-rectal cancer.


Assuntos
Anticarcinógenos/farmacologia , Butiratos/farmacologia , Neoplasias Colorretais/prevenção & controle , Fibras na Dieta/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Carboidratos da Dieta , Humanos , Análise Serial de Proteínas , Proteômica , Amido/administração & dosagem
19.
Proc Natl Acad Sci U S A ; 99(14): 9433-8, 2002 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-12093899

RESUMO

Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.


Assuntos
Neoplasias Colorretais/genética , Genes APC , Genes p53 , Genes ras , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutação
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