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1.
Development ; 141(18): 3505-16, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25183869

RESUMO

During vertebrate gastrulation, a complex set of mass cellular rearrangements shapes the embryonic body plan and appropriately positions the organ primordia. In zebrafish and Xenopus, convergence and extension (CE) movements simultaneously narrow the body axis mediolaterally and elongate it from head to tail. This process is governed by polarized cell behaviors that are coordinated by components of the non-canonical, ß-catenin-independent Wnt signaling pathway, including Wnt5b and the transmembrane planar cell polarity (PCP) protein Vangl2. However, the intracellular events downstream of Wnt/PCP signals are not fully understood. Here, we show that zebrafish mutated in colorectal cancer (mcc), which encodes an evolutionarily conserved PDZ domain-containing putative tumor suppressor, is required for Wnt5b/Vangl2 signaling during gastrulation. Knockdown of mcc results in CE phenotypes similar to loss of vangl2 and wnt5b, whereas overexpression of mcc robustly rescues the depletion of wnt5b, vangl2 and the Wnt5b tyrosine kinase receptor ror2. Biochemical experiments establish a direct physical interaction between Mcc and the Vangl2 cytoplasmic tail. Lastly, CE defects in mcc morphants are suppressed by downstream activation of RhoA and JNK. Taken together, our results identify Mcc as a novel intracellular effector of non-canonical Wnt5b/Vangl2/Ror2 signaling during vertebrate gastrulation.


Assuntos
Gastrulação/fisiologia , Genes MCC/genética , Morfogênese/fisiologia , Via de Sinalização Wnt/fisiologia , Peixe-Zebra/embriologia , Animais , Western Blotting , Polaridade Celular/fisiologia , Imunoprecipitação , Hibridização In Situ , Luciferases , Proteínas de Membrana/metabolismo , Microscopia Confocal , Domínios PDZ/genética , Reação em Cadeia da Polimerase , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Proteínas Wnt/metabolismo , Proteína Wnt-5a , Proteínas de Peixe-Zebra/metabolismo
2.
J Hematol Oncol ; 7: 56, 2014 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-25200342

RESUMO

BACKGROUND: Identification of novel genetic risk factors is imperative for a better understanding of B lymphomagenesis and for the development of novel therapeutic strategies. TRAF3, a critical regulator of B cell survival, was recently recognized as a tumor suppressor gene in B lymphocytes. The present study aimed to identify novel oncogenes involved in malignant transformation of TRAF3-deficient B cells. METHODS: We used microarray analysis to identify genes differentially expressed in TRAF3-/- mouse splenic B lymphomas. We employed lentiviral vector-mediated knockdown or overexpression to manipulate gene expression in human multiple myeloma (MM) cell lines. We analyzed cell apoptosis and proliferation using flow cytometry, and performed biochemical studies to investigate signaling mechanisms. To delineate protein-protein interactions, we applied affinity purification followed by mass spectrometry-based sequencing. RESULTS: We identified mutated in colorectal cancer (MCC) as a gene strikingly up-regulated in TRAF3-deficient mouse B lymphomas and human MM cell lines. Aberrant up-regulation of MCC also occurs in a variety of primary human B cell malignancies, including non-Hodgkin lymphoma (NHL) and MM. In contrast, MCC expression was not detected in normal or premalignant TRAF3-/- B cells even after treatment with B cell stimuli, suggesting that aberrant up-regulation of MCC is specifically associated with malignant transformation of B cells. In elucidating the functional roles of MCC in malignant B cells, we found that lentiviral shRNA vector-mediated knockdown of MCC induced apoptosis and inhibited proliferation in human MM cells. Experiments of knockdown and overexpression of MCC allowed us to identify several downstream targets of MCC in human MM cells, including phospho-ERK, c-Myc, p27, cyclin B1, Mcl-1, caspases 8 and 3. Furthermore, we identified 365 proteins (including 326 novel MCC-interactors) in the MCC interactome, among which PARP1 and PHB2 were two hubs of MCC signaling pathways in human MM cells. CONCLUSIONS: Our results indicate that in sharp contrast to its tumor suppressive role in colorectal cancer, MCC functions as an oncogene in B cells. Our findings suggest that MCC may serve as a diagnostic marker and therapeutic target in B cell malignancies, including NHL and MM.


Assuntos
Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Genes MCC/genética , Oncogenes/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Imunoprecipitação da Cromatina , Citometria de Fluxo , Humanos , Immunoblotting , Imunoprecipitação , Linfoma não Hodgkin/genética , Camundongos , Camundongos Knockout , Mieloma Múltiplo/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proibitinas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator 3 Associado a Receptor de TNF/deficiência , Espectrometria de Massas em Tandem
3.
J Oral Pathol Med ; 32(8): 450-4, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12901725

RESUMO

BACKGROUND: Loss of heterozygosity (LOH) at tumor suppressor genes, such as adenomatous polyposis coli (APC) and mutated in colon cancer (MCC) genes, is one of the early events in carcinogenesis of oral tissue in Caucasian and Chinese patients. We wanted to check whether it is also true in Indian oral pre-cancer and cancer patients. METHODS: Loss of heterozygosity at APC and MCC genes was investigated in 57 and 40 unrelated primary oral leukoplakia (a pre-cancerous lesion) and squamous cell carcinomas (SCC), respectively, by polymerase chain reaction. RESULTS: In these samples, most of the leukoplakia patients had tobacco smoking habit whereas majority of cancer patients had tobacco chewing habit. LOH at APC gene was observed in 4 of 16 (25%) and 1 of 29 (3%) informative tumor and leukoplakia DNAs from tobacco chewers, respectively. LOH at MCC gene was not detected either in tumor or in leukoplakia DNAs. CONCLUSION: This infrequent LOH at APC gene of pre-cancer and cancer tissues suggests that it may not be an early event in oral carcinogenesis in these patients.


Assuntos
Genes APC , Genes MCC/genética , Leucoplasia Oral/genética , Perda de Heterozigosidade/genética , Neoplasias Bucais/genética , Tabaco sem Fumaça/efeitos adversos , Adulto , Idoso , Areca/efeitos adversos , Carcinoma de Células Escamosas/genética , DNA de Neoplasias/genética , Feminino , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Lesões Pré-Cancerosas/genética , Fumar/efeitos adversos
4.
Digestion ; 63(4): 229-33, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11435722

RESUMO

BACKGROUND: The adenoma-carcinoma sequence has its molecular basis in several gene mutations of which K-ras and p53 are of paramount importance. The aims of this study were to evaluate whether these genetic alterations can be detected in colonic lavage fluid from patients with colorectal adenomas and carcinomas. METHODS: In 45 patients with adenomas, 20 patients with colorectal carcinomas and 38 patients with non-neoplastic and noninflammatory diseases of the colon p53 and K-ras mutations were evaluated in colonic lavage fluid employing single-strand confirmation polymorphism analysis and dot-blot hybridization, respectively. RESULTS: Mutations of the K-ras and the p53 gene were found in 15.6% (p = 0.065) of patients with adenomas, in 25.0 % (p = 0.016) of patients with carcinomas and in 2.6% in the control group. CONCLUSION: Genetic alterations in the colonic lavage fluid could be an additional diagnostic tool for the surveillance of patients with colorectal neoplasias.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Genes p53/genética , Genes ras/genética , Idoso , Idoso de 80 Anos ou mais , Líquidos Corporais/metabolismo , Colo/metabolismo , Feminino , Genes MCC/genética , Genes Supressores de Tumor/genética , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Reação em Cadeia da Polimerase , Irrigação Terapêutica
5.
G Chir ; 20(8-9): 373-7, 1999.
Artigo em Italiano | MEDLINE | ID: mdl-10444928

RESUMO

The Authors point out the basis for a better characterisation of colo-rectal cancer and precursory lesions. In fact the etiology of familial adenomatous polyposis (FAP), aberrant crypt foci (ACF), hereditary non polyposis colon cancer syndrome (HNPCC) seems to be correlated to molecular pathology. Therefore the Authors review colo-rectal cancer natural history which frequently appears to be not related to clinical evolution.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Genes DCC/genética , Genes MCC/genética , Humanos , Biologia Molecular , Pesquisa
6.
Diagn Mol Pathol ; 8(1): 2-10, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10408787

RESUMO

A comprehensive mutation detection assay is described for the entire coding region and all splice site junctions of TP53. The assay is based on denaturing gradient gel electrophoresis, which follows either multiplex polymerase chain reaction (PCR) applied to DNA extracted from fresh or frozen tissue samples or nested PCR applied to DNA extracted from paraffin-embedded tissue samples. In both instances, the analysis can be performed under a single set of conditions. When testing the assay on DNA from cultured lung cancer cell lines and from paraffin-embedded Dukes C colorectal carcinomas, significant TP53 mutations were observed at high frequencies in 15 of 16 lung cancer cell lines (94%) and in 21 of 30 paraffin-embedded tissue samples of Dukes C colorectal carcinomas (70%). A substantial proportion of these significant mutations occurred outside the evolutionary conserved region of TP53 in 4 of 16 lung cancer cell lines (25%) and in 11 of 30 paraffin-embedded colorectal carcinomas (37%). This underscores the importance of a comprehensive TP53 mutation analysis in those instances that TP53 mutation is taken into account for diagnostic and prognostic purposes.


Assuntos
DNA de Neoplasias/genética , Eletroforese em Gel de Poliacrilamida/métodos , Genes p53 , Mutação/genética , Neoplasias Colorretais/química , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Primers do DNA/química , DNA de Neoplasias/análise , DNA Recombinante , Genes MCC/genética , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Inclusão em Parafina , Reação em Cadeia da Polimerase , Células Tumorais Cultivadas
7.
Ned Tijdschr Geneeskd ; 143(23): 1207-11, 1999 Jun 05.
Artigo em Holandês | MEDLINE | ID: mdl-10389535

RESUMO

About 15% of patients with colorectal cancer have a positive family history: 5% have hereditary colorectal cancer (hereditary non-polyposis colorectal carcinoma (HNPCC), familial adenomatous polyposis (FAP) or some other hereditary syndrome), while in 10% no clear hereditary pattern can be recognized ('familial colorectal cancer'). In sporadic and in familial intestinal cancer, a demonstrable hereditary predisposition may undoubtedly exist. HNPCC is often characterized by microsatellite instability, i.e. an increased number of short DNA sequences in the DNA indicating a disorder in DNA repair and a mutation in a DNA 'mismatch repair' (MMR) gene. Indicative of hereditary bowel cancer on the basis of such an MMR gene mutation are: (a) presence of bowel cancer in > or = 3 relatives, (b) early age at the time of the diagnosis of 'bowel cancer', (c) multiple primary bowel tumours, (d) uterine cancer in the family and (e) bowel and uterine cancer in a woman. Recent data demand a new subdivision of hereditary bowel cancer, based upon both the clinical picture and the results of DNA-tests. The genetic alterations in colonic adenomas and carcinomas are known to a large extent. In future these insights may be important in clinical practice, such as a more individual determination of the patient's prognosis and accordingly, of the treatment and follow-up.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Primárias Múltiplas/genética , Adenoma/genética , Adolescente , Adulto , Idoso , Pareamento Incorreto de Bases , Carcinoma/genética , Criança , Pré-Escolar , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Análise Mutacional de DNA , Reparo do DNA/genética , Feminino , Genes MCC/genética , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Síndrome , Neoplasias Uterinas/genética
8.
Mol Carcinog ; 21(1): 37-49, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9473770

RESUMO

A decrease in the intracellular concentrations of the transcripts for some tumor suppressor genes has been found during murine lung tumorigenesis; for p15INK4b and p16INK4a, this was due to homozygous deletions. We report here a decrease in the mRNA levels of the mutated in colorectal cancer (Mcc) and adenomatous polyposis coli (Apc) genes in mouse lung tumors and some neoplastic cell lines. This was assessed both by northern blotting and reverse transcriptase-polymerase chain reaction of RNA isolated from lung tumors that had been induced by urethane, N-nitrosodiethylamine, or 3-methylcholanthrene in (A/J x C57BL/6) F1 or A/J mice. A reduced amount of both Mcc and Apc messages was also seen when two neoplastic cell lines, a spontaneous transformant (E9) and a line derived from a chemically induced solid tumor (82-132), were compared with two independently derived nontumorigenic cell lines (E10 and C10); E9 was derived from E10, and all of these lines are probably of alveolar type 2 cell origin. A cell line derived from a chemically induced papillary lung tumor probably of bronchiolar Clara cell origin (LM2) had Mcc mRNA levels similar to those of C10 and E10 but reduced Apc mRNA levels. A line (p53-823) derived from a papillary tumor that arose in a mouse with a mutated p53 transgene had a reduced amount of the Mcc gene product only. These differential changes in the relative amounts of Apc and Mcc messages in LM2 and p53-823) cells may serve as useful models for studying the regulation of their expression. Both messages had half-lives of 6-9 h in normal E10 and neoplastic E9 cells, so decreased message stability does not account for these reductions. This is the first report of estimated degradation rates of these mRNAs. Apc and Mcc message content did not vary as a function of growth status of the cell lines. Single-strand conformation polymorphism analysis did not reveal mutations in Apc coding regions known to have a high mutation frequency in human colon tumors. Loss of heterozygosity of Apc and Mcc was not found in tumors that developed in the F1 mice, implying a lack of allelic deletions. These changes in tumor suppressor gene expression may contribute to the development and maintenance of neoplasia in lung epithelium.


Assuntos
Células Epiteliais/metabolismo , Genes APC/genética , Genes MCC/genética , Neoplasias Pulmonares/genética , RNA Mensageiro/metabolismo , Animais , Regulação para Baixo , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Tumorais Cultivadas
9.
J Oral Pathol Med ; 26(7): 322-6, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9250932

RESUMO

Loss of heterozygosity (LOH) at adenomatous polyposis coli (APC) and mutated in colon cancer (MCC) genes was investigated in 37 untreated human primary oral squamous cell carcinomas (SCCs) using the polymerase chain reaction. LOH was observed in 14 of 26 (53.8%) heterozygous (informative) patients at APC and 9 of 13 (69.2%) heterozygous patients at MCC> Homozygous deletion of MCC was detected in one patient. Of the 37 patients, 29 were informative at APC or MCC or both; LOH at APC and/or MCC was detected in 68.9% (20/29) of the cases. Ten cases were informative for both genes; LOH at both loci was found in only three of these cases. LOH at the APC and/or MCC was found in both early and advanced stages of oral SCCs. No significant correlation was observed between LOH at the APC and/or MCC locus and the patients' tobacco/betel quid consumption, tumour location, TNM status, or histological differentiation. These results suggest that LOH at the APC and/or MCC may be an early event and may play a role in the pathogenesis of human oral SCCs in Taiwan.


Assuntos
Carcinoma de Células Escamosas/genética , Deleção Cromossômica , Genes APC/genética , Genes MCC/genética , Neoplasias Bucais/genética , Heterozigoto , Humanos , Reação em Cadeia da Polimerase , Taiwan
10.
Hematol Oncol Clin North Am ; 11(4): 609-33, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9257148

RESUMO

The enormous progress made in the identification of genes that are involved in colon carcinogenesis has provided the foundation for further understanding the biology of both normal and cancer cells and for targeted therapeutic strategies. In one sense, the genes described in this review are only the building blocks of a larger puzzle that constitutes the integrated metabolic function of a cell. The current challenge is to understand the functional role of these genes in normal cellular physiology and make the connections between pathways that knit together integrated cellular homeostasis. A complete understanding of the regulatory pathways, and the synthesis and modifications of the proteins involved, will provide novel targets for therapeutic agents.


Assuntos
Neoplasias Colorretais/genética , Genes Supressores de Tumor/genética , Adenoma/genética , Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , Genes APC/genética , Genes DCC/genética , Genes MCC/genética , Genes p53/genética , Humanos , Receptores de Hialuronatos/genética , Mutação , Transdução de Sinais
11.
Br J Cancer ; 74(7): 1104-8, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8855982

RESUMO

We examined 26 gastric carcinomas from British patients for mutations of the APC gene using a single-strand conformation polymorphism (SSCP) and heteroduplex assay in conjunction with the protein truncation test (PTT). In addition, we performed loss of heterozygosity (LOH) analysis of the APC and MCC genes. We detected an inactivating somatic mutation in one gastric tumour. LOH of APC was observed in one of 12 informative cases (8%) and of MCC in two of 20 cases (10%). We thus find that alteration of the APC and MCC genes are infrequent in gastric cancers from the British population. Tumour-suppressor genes on other chromosomes must play a more significant role in the development of these tumours.


Assuntos
Genes APC/genética , Genes MCC/genética , Mutação Puntual/genética , Neoplasias Gástricas/genética , Proteína da Polipose Adenomatosa do Colo , Alelos , Sequência de Bases , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/química , Inglaterra/etnologia , Deleção de Genes , Humanos , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Deleção de Sequência , Neoplasias Gástricas/química , Neoplasias Gástricas/etnologia
12.
Zhonghua Zhong Liu Za Zhi ; 18(1): 3-5, 1996 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-8732100

RESUMO

In order to detect loss of heterozygosity (LOH) at APC and MCC genetic loci in gastric carcinoma, the authors established a micro-wax-mediated hot start PCR technique. This method allowed a specific gene amplification, and it was useful especially in the amplification of formalin-fixed or stained tissues. In 44 cases of gastric cancer, 29 cases were informative of the APC locus. LOH was found in 8 cases (27.6%): 2 cases in 2 moderately well-differentiated cancer, 2 cases in 13 differentiated cancer, and 4 cases in poorly-differentiated cancer. One of the 3 cases of gastric cancer at early stage also showed LOH. LOH at MCC locus was detected in only 2 of the 25 (8.0%) gastric cancer patients informative. These data suggest that abnormality of APC gene plays a role in the tumorigenesis of gastric cancer and the change may occur at the early stage of tumor development.


Assuntos
Adenocarcinoma/genética , Deleção de Genes , Genes APC/genética , Genes MCC/genética , Neoplasias Gástricas/genética , Heterozigoto , Humanos
13.
Cancer Res ; 55(2): 220-3, 1995 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-7812947

RESUMO

We investigated the frequency and clinical significance of loss of heterozygosity (LOH) at the APC, MCC, and DCC tumor suppressor gene loci in 108 cases of resected non-small cell lung cancer (NSCLC). LOH at the APC/MCC gene cluster at chromosome 5q21 occurred frequently; it affected 29% of informative NSCLC cases and correlated with a significantly worse survival (P < 0.01). Furthermore, in the subtype most frequently affected (SCC), LOH at 5q not only correlated with a worse survival but also tumor involvement of the mediastinal and/or hilar nodes. In contrast, LOH at the DCC locus at chromosome 18q was far less frequent, occurring in 14% of NSCLC cases, and it was not associated with advanced stage or prognosis. These data suggest that LOH at 5q has a role in determining tumor progression and survival in NSCLC, and may prove to be a clinically useful prognostic indicator.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 5/genética , Deleção de Genes , Genes APC/genética , Genes DCC/genética , Genes MCC/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Annu Rev Med ; 46: 371-9, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7598472

RESUMO

The genes that are mutated in two of the rare syndromes of hereditary colon cancer were recently identified, and genetic diagnosis is already possible in some cases. Acquired mutations of these same genes also appear to be important in sporadic colon cancers. Familial clustering of sporadic cases is common and may likewise arise from inherited susceptibility. Screening strategies for both the rare syndromes and the common cases of colon cancer with familial risk have been suggested. Certain clinical features allow stratification of colon cancer risk among common cases. It is anticipated that continued genetic investigation will result in more precise screening and improved diagnostic and therapeutic options for colon cancer.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Análise Mutacional de DNA , Genes DCC/genética , Genes MCC/genética , Testes Genéticos , Humanos , Biologia Molecular , Fatores de Risco
16.
Zhonghua Zhong Liu Za Zhi ; 17(1): 9-12, 1995 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-7656796

RESUMO

The mutation and deletion of APC, MCC genes in human esophageal cancer were analyzed by PCR amplification and direct sequencing assay. In PCR amplification analysis, one of 10 cases of esophageal cancer was found to have APC gene deletion in exon 11; one of 10 cases of EC was found to have MCC gene deletion in exon 12; one case of EC was found to have MCC gene deletion in exon 12. One of adjacent non-tumor tissue was also found to have deletion at exon 12 of MCC. In PCR direct sequencing analysis, two of 10 cases of EC were found to contain APC gene mutation in exon 11, two of 7 cases of EC were found to contain MCC genes mutation in exon 12. The results confirmed that mutation of APC and MCC genes exists in human esophageal cancer. It gives new clues to the understanding of carcinogenesis of human esophageal cancer. The mechanism of mutation or deletion of APC and MCC genes in EC needs further study.


Assuntos
Neoplasias Esofágicas/genética , Deleção de Genes , Genes APC/genética , Genes MCC/genética , Mutação Puntual , Sequência de Bases , DNA de Neoplasias/genética , Éxons , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
19.
Br J Cancer ; 70(5): 813-8, 1994 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7947085

RESUMO

We report here the use of multiplex fluorescent polymerase chain reaction (PCR) for quantitative allele loss detection using microsatellites with 2-5 base pair repeat motifs. Allele loss of APC, DCC, p53 and RB1 in colorectal tumours has been reported previously using a variety of methods. However, not all workers used intragenic markers. We have used microsatellite polymorphisms which map within, or are closely linked to, these tumour-suppressor gene loci in order to determine whether these loci are indeed the targets for alteration in colorectal cancer. In addition, we have assayed two other tumour-suppressor genes, WT1 and NF1, to see whether they play a role in colorectal carcinogenesis. The putative metastasis-suppressor gene, NM23, was also investigated since there have been conflicting reports about its involvement in colorectal carcinogenesis. Allele loss was detected at the DCC (29%), p53 (66%), RB1 (50%) and NF1 (14%) loci and in the APC/MCC region (50%), but not at the WT1 or NM23 loci. These rapid, and mostly gene-specific, fluorescent multiplex PCR assays for allele loss detection could be modified to devise a single molecular diagnostic test for the important lesions in colorectal cancer.


Assuntos
Adenocarcinoma/genética , Alelos , Neoplasias Colorretais/genética , Deleção de Genes , Genes Supressores de Tumor , Proteínas Monoméricas de Ligação ao GTP , Núcleosídeo-Difosfato Quinase , Reação em Cadeia da Polimerase/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , DNA Satélite/análise , DNA Satélite/genética , Feminino , Fluorescência , Genes APC/genética , Genes DCC/genética , Genes MCC/genética , Genes da Neurofibromatose 1/genética , Genes do Retinoblastoma/genética , Genes do Tumor de Wilms , Genes p53/genética , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Nucleosídeo NM23 Difosfato Quinases , Polimorfismo Genético , Sensibilidade e Especificidade , Fatores de Transcrição/genética
20.
Cancer Epidemiol Biomarkers Prev ; 3(4): 331-3, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8061582

RESUMO

Tumor suppressor genes APC and MCC were identified recently, and their chromosomal location was ascribed to chromosome 5q21. Mutations in the APC gene give rise to familial adenomatous polyposis and occur in many perhaps even the majority, of sporadic colon cancers. Loss of heterozygosity has been described in other human tumors such as lung and esophageal cancers. Here we show loss of heterozygosity (LOH) in 87 patients with breast cancer for the APC and/or MCC loci using a polymerase chain reaction-LOH assay. LOH affected loci in APC exons 11 and 15 in 9 of 35 (25%) and 4 of 34 (11%) heterozygous patients, respectively. LOH at the MCC exon 10 locus occurred in 7 of 40 (17%) informative samples. These data suggest that allelic deletion of APC and/or MCC is probably involved in the pathogenesis and/or progression of a subset of breast cancers.


Assuntos
Neoplasias da Mama/genética , Deleção Cromossômica , Genes APC/genética , Genes MCC/genética , Sequência de Bases , DNA de Neoplasias/análise , Éxons , Feminino , Heterozigoto , Humanos , Dados de Sequência Molecular , Mutação , Reação em Cadeia da Polimerase
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