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1.
Acta Oncol ; 47(6): 1046-53, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17943475

RESUMO

BACKGROUND: Colorectal cancer (CRC) cell lines displaying microsatellite instability (MSI) are resistant to 5-fluorouracil (5-FU) in vitro, which can be overcome by restoring DNA mismatch repair (MMR) competence. Thymidylate synthase (TS) is inhibited by 5-FU, being another potential mediator of therapeutic resistance to 5-FU. The clinical relevance of these observations remains unclear. OBJECTIVE: We examined the expression of TS and two MMR proteins (hMLH1 and hMSH2) in advanced CRC patients, to determine a) their mutual relationship, b) association to therapeutic response and c) impact on disease outcome. MATERIAL AND METHODS: Tumour samples from 73 patients CRC who were treated in advanced stage with either irinotecan alone or in combination with 5-FU/leucovorin, were analysed for expression of TS, hMLH1 and hMSH2 using immunohistochemistry (IHC). RESULTS: TS expression was closely correlated with hMLH1 expression (negative-weak/moderate-strong) (p=0.0001). TS-MMR expression was significantly (p=0.029 for whole series; p=0.004 for the 5-FU treated cases) related to response to treatment; tumours with low levels of both TS and MMR responded better (n=14/27, 51.8%) than those with high TS and MMR (n=3/18, 16.6%). Patients with high TS-MMR expression had a significantly longer DFS (47 months vs. 9 months, n=26) than those with low TS-MMR index (p=0.015), while the reverse was true concerning survival with metastases (WMS) (p=0.018) in all the patients (n=73). CONCLUSIONS: The present data suggest that MSI patients with low TS and deficient MMR demonstrate a significantly shorter DFS and longer WMS than patients with high expression of both markers, and they are also more likely to obtain the greatest benefit from 5-FU based chemotherapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Proteína 2 Homóloga a MutS/análise , Proteínas Nucleares/análise , Timidilato Sintase/análise , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Fluoruracila/administração & dosagem , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Irinotecano , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites/efeitos dos fármacos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/efeitos dos fármacos , Proteína 2 Homóloga a MutS/genética , Estadiamento de Neoplasias , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/genética , Timidilato Sintase/efeitos dos fármacos , Timidilato Sintase/genética , Resultado do Tratamento
2.
Tumour Biol ; 28(4): 212-20, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17717427

RESUMO

BACKGROUND AND AIMS: To determine the association between DNA mismatch repair (MMR) protein expression and response to chemotherapy in patients with advanced colorectal cancer (CRC). METHODS: Using immunohistochemistry, tumour expression of 2 MMR genes, hMLH1 and hMSH2, was assessed in 86 patients with advanced CRC, who were treated with either irinotecan alone or in combination with 5-flurouracil/folinic acid. RESULTS: Weak/negative staining in the tumours was associated with the presence of metastases at diagnosis (p = 0.026) and with the time for metastases to appear (p = 0.0001). An objective response to treatment was observed in 32/56 (57%) patients who had tumours with negative/weak MMR protein expression (p = 0.001), compared to 17% of patients with tumours with moderate/strong expression. Those who had tumours with weak/absent expression of either hMLH1 or hMSH2 who received the combination therapy were more likely to show an objective response (p = 0.0001). CONCLUSION: Advanced CRC patients whose tumours have deficient MMR demonstrate a shorter time to metastasis than those with normal hMLH1/hMSH2 expression. Patients with MMR-deficient tumours are also more likely to benefit from combination chemotherapy (irinotecan plus 5-flurouracil/folinic acid).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pareamento Incorreto de Bases , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Reparo do DNA , Fluoruracila/administração & dosagem , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Idoso , Camptotecina/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/biossíntese , Metástase Neoplásica , Proteínas Nucleares/biossíntese , Resultado do Tratamento
3.
Oncol Rep ; 16(4): 741-6, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16969488

RESUMO

A better understanding on the development of a metastatic phenotype in colorectal cancer (CRC) is essential to help identify patients at high risk for metastasis. Therefore, we have studied the role of the CD44 family of trans-membrane glycoprotein in the process of CRC metastasis, by examining the expression of CD44s and CD44v6 in primary tumours and their metastatic lesions in 46 patients using immunohistochemistry. The expression of both CD44s and CD44v6 was significantly higher (moderate/strong) in primary tumours as compared to their metastases (p=0.008, p=0.0001, respectively). CD44s expression in metastases increased with the degree of the histological grade (p=0.009) and invasiveness of the primary tumour (p=0.002). Disease-free survival (DFS) was shorter in patients who had metastases with a strong/moderate expression of CD44s as compared to those with negative/weak expression (8.3 months vs 16.9 months p=0.221, respectively). Our finding that CD44s expression in metastatic lesions may reflect the aggressiveness of the primary tumour from which it has originated implicates an important link between the two lesions. CD44 expression may also provide valuable biological information as suggested by the observation that up-regulated CD44s expression in metastases is associated with a shorter DFS.


Assuntos
Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores de Hialuronatos/biossíntese , Neoplasias/metabolismo , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Glicoproteínas/biossíntese , Humanos , Imuno-Histoquímica , Masculino , Metástase Neoplásica , Fatores de Tempo
4.
Oncol Rep ; 14(3): 657-62, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16077970

RESUMO

Thymidylate synthase (TS) is the rate-limiting enzyme in the synthesis of pyrimidine nucleotides, required for DNA synthesis, and is also a critical target for fluoropyrimidines, which are widely used in the treatment of gastrointestinal tumours. We examined TS expression in tumours from 86 patients with advanced colorectal cancer who received one of two chemotherapy regimes (either irinotecan alone or irinotecan and 5-flurouracil with folinic acid). TS expression was determined immunohistochemically in 86 paraffin-embedded primary tumour sections and assessed using image analysis software. TS was significantly associated with survival, with lower levels of TS expression associated with longer patient survival (p=0.02). Patients with an objective response to treatment had a longer median survival than those who did not show an objective response to treatment (p=0.001). A significant association was found between tumour TS expression and response to treatment with 5-FU plus FA with irinotecan (p=0.05). Sixty-four percent of patients with TS expression levels below the median showed an objective (complete or partial) response to treatment while, 38% with TS expression levels above the median responded. Immunohistochemical TS expression levels might be used both as a prognostic marker and to help identify patients who would benefit from 5-FU based regime.


Assuntos
Neoplasias Colorretais/patologia , Timidilato Sintase/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Feminino , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Análise de Sobrevida
5.
Oncol Rep ; 13(5): 831-5, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15809746

RESUMO

Cell adhesion molecules (CAMs) are cell surface glycoproteins that are important in cell-cell and cell-matrix interactions and play an important role in cell growth and differentiation. We examined immunohistochemically CD44s, CD44v6 and E-cadherin expression in 86 formalin-fixed, paraffin-embedded primary tumours and 5 metastases. Lower levels of CD44s, CD44v6 and membranous E-cadherin expression were significantly associated with higher tumour grade (p=0.022, p=0.016 and p= 0.041, respectively). Moreover, CD44v6 and membranous E-cadherin expression were correlated with the depth of primary tumour invasion (p=0.030 and p=0.020, respectively), and increased expression of CD44v6 and decreased membranous E-cadherin expression were associated with increased primary tumour invasion. The results suggest that these CAMs are associated with tumour differentiation and invasion in locally advanced and metastatic colorectal carcinoma.


Assuntos
Caderinas/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Glicoproteínas/metabolismo , Receptores de Hialuronatos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/imunologia , Carcinoma/mortalidade , Carcinoma/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Análise de Sobrevida , Fatores de Tempo
6.
Anticancer Res ; 24(4): 2519-30, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15330208

RESUMO

Tumour markers are molecules occurring in blood or tissue that are associated with cancer and whose measurement or identification is useful in patient diagnosis or clinical management. The ideal marker would occur only in patients with malignancy, and would correlate with stage and response to treatment, however, to date there are few reliable prognostic markers in colorectal cancer (CRC), consequently much research is focused on identifying such markers. This review aims to summarise the most important currently available markers in CRC that provide prognostic or predictive information. Amongst others, it covers serum markers such as CEA and CA19-9, markers expressed in tumour tissue such as thymidylate synthase and also the expression/loss of expression of certain oncogenes and tumour suppressor genes such as K-ras and p53. The prognostic value of genomic instability, angiogenesis and proliferative indices such as apoptotic index is discussed.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Humanos , Valor Preditivo dos Testes , Prognóstico
7.
Oncology ; 66(1): 46-52, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15031598

RESUMO

OBJECTIVE: The aim of this study was to identify markers that might predict response to chemotherapy. Postoperative chemotherapy improves the outcome in stage III colon cancer and is widely accepted as a standard therapy, but there are currently no reliable predictors to identify and select patients that will benefit. METHODS: Using DNA image cytometry, the DNA content was determined from the isolated nuclei of 56 primary colorectal carcinomas of patients who received chemotherapy (either irinotecan or irinotecan plus 5-fluorouracil and folinic acid) for advanced disease. Response to chemotherapy could be reliably evaluated in 53 patients. RESULTS: The modal DNA content (ploidy status) of the tumour correlated with the observed response to chemotherapy (p = 0.01). An objective response was observed in 56% of patients whose tumour histograms displayed tetraploid, peri-tetraploid or multiploid patterns of peaks, compared with 19% in patients with diploid, peri-diploid or aneuploid peaks. Notably, 86% (6/7) of patients whose tumours displayed a multiploid peak pattern showed an objective response and 1 patient had stable disease. CONCLUSIONS: This study suggests that modal DNA content can be used to predict a patient's response to chemotherapy in advanced colorectal carcinoma. This may help in identifying patients who will benefit most from therapy for advanced colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/análise , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , DNA de Neoplasias/análise , DNA de Neoplasias/efeitos dos fármacos , Adulto , Idoso , Camptotecina/farmacologia , Neoplasias Colorretais/cirurgia , Feminino , Fluoruracila/farmacologia , Humanos , Irinotecano , Leucovorina/farmacologia , Masculino , Pessoa de Meia-Idade , Ploidias , Valor Preditivo dos Testes , Resultado do Tratamento
8.
Oncol Rep ; 11(1): 41-5, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14654900

RESUMO

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. CD44 variant 6 (CD44v6) has been postulated to be involved in both carcinogenesis and tumor progression. Therefore, we have examined CD44v6 expression in tumors from 57 patients with advanced colorectal cancer who received one of two chemotherapy regimes (either irinotecan alone or irinotecan and 5-flurouracil with folinic acid). CD44v6 expression was determined immunohistochemically in 57 paraffin-embedded primary tumor sections and assessed using image analysis software. Strong expression levels of CD44v6 were seen in 24/57 (42%) of tumors, moderate levels in 17/57 (30%), weak levels in 9/57 (16%) and no expression was seen in 7/57 (12%). The pattern of staining was predominantly cytoplasmic, 7/57 tumors also exhibited membrane specific expression. A significant association was found between tumor CD44v6 expression and treatment response (Fisher's exact test p=0.01). Only 1/12 patients with no or weak tumor expression of CD44v6 showed a response to treatment whereas 20/41 (49%) patients with moderate or strong CD44v6 expression responded to treatment. Evaluation of CD44v6 expression of locally advanced and metastatic colorectal tumors may enable the clinician to identify and select patients that will show the best response to irinotecan based chemotherapy.


Assuntos
Neoplasias Colorretais/patologia , Glicoproteínas/biossíntese , Receptores de Hialuronatos/biossíntese , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Imuno-Histoquímica , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Análise de Sobrevida
9.
Oncology ; 64(4): 435-42, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12759543

RESUMO

OBJECTIVES: To examine programmed cell death in 57 colorectal carcinomas (49 primary tumours and 8 metastases) and determine the prognostic significance of apoptosis in colorectal cancer. METHODS: Apoptotic index (AI) was ascertained by counting apoptotic bodies, using terminal deoxynucleotidyl transferase mediated digoxigenin nick end labelling (Tunel assay) and the expression of bcl-2 was examined immunohistochemically. Statistical analysis was used to test the value of clinical variables, histopathological data, AI and bcl-2 expression in predicting the clinical outcome of these patients and the survival function was calculated using the Kaplan-Meier method. RESULTS: AI was found to have a significant independent effect on survival (p = 0.0006), with lower values of AI conveying better survival. CONCLUSION: In summary, these findings reveal that AI is a useful prognostic factor in colorectal carcinoma.


Assuntos
Apoptose , Biomarcadores Tumorais/análise , Carcinoma/química , Carcinoma/patologia , Neoplasias Colorretais/química , Neoplasias Colorretais/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Adulto , Idoso , Carcinoma/secundário , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida
10.
Oncology ; 65(4): 337-46, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14707454

RESUMO

OBJECTIVE: Extracellular matrix degradation is required for invasive growth and metastasis formation in colorectal carcinoma; therefore, we examined matrix metalloproteinases expression (MMP-1, MMP-13 and MT1-MMP) and apoptosis in tumours from 49 patients with advanced colorectal disease. METHODS: MMP expression was determined immunohistochemically and apoptotic index (AI) was ascertained using the TUNEL assay. RESULTS: Low levels of MT1-MMP, MMP-1 and AI were found to be favourable markers significantly associated with longer survival. MT1-MMP expression levels below the median (

Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 1 da Matriz/análise , Metaloendopeptidases/análise , Adulto , Idoso , Colagenases/análise , Feminino , Humanos , Masculino , Metaloproteinase 13 da Matriz , Metaloproteinases da Matriz Associadas à Membrana , Pessoa de Meia-Idade , Análise de Sobrevida
11.
Proc Natl Acad Sci U S A ; 99(26): 16910-5, 2002 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-12486240

RESUMO

In vitro data show that the adenomatous polyposis coli (APC) protein associates with the mitotic spindle and that mouse embryonic stem cells with biallelic Apc mutations are karyotypically unstable. These findings led to suggestions that APC acts in chromosomal segregation and that APC inactivation leads to chromosomal instability (CIN). An alternative hypothesis based on allelic loss studies in colorectal adenomas proposes that CIN precedes and contributes to genetic changes at APC. We determined whether colorectal adenomas with two mutations at APC show features consistent with these models by studying 55 lesions (average size 5 mm; range 1-13 mm) from patients with familial adenomatous polyposis. A variety of methods was used depending on available material, including flow cytometry, comparative genomic hybridization, and loss of heterozygosity (LOH) analysis. Selected adenomas were assessed for proliferative activity by Ki-67 immunocytochemistry. Seventeen of 20 (85%) tumors were diploid, two were near-diploid, and one was hypotetraploid. Just one (near-diploid) tumor showed increased proliferative activity. LOH was found occasionally on chromosome 15q (2 of 49 tumors), but not on chromosome 18q (0 of 48). In 20 adenomas, LOH at APC was associated with loss at 5q but not 5p markers, with the former encompassing a minimum of 20 Mb. However, three of these lesions analyzed by comparative genomic hybridization displayed normal profiles, suggesting, together with other data, that the mechanism of LOH at APC is probably somatic recombination. Our results therefore do not support the hypothesis that CIN precedes APC mutations in tumorigenesis. Regarding the model in which APC mutations lead directly to CIN, if APC mutations do have this effect in vivo, it must be subtle. Alternatively, CIN associated with APC mutations might be essentially an in vitro phenomenon.


Assuntos
Adenoma/genética , Aberrações Cromossômicas , Neoplasias Colorretais/genética , Genes APC , Mutação , Humanos , Antígeno Ki-67/análise , Perda de Heterozigosidade
12.
Proc Natl Acad Sci U S A ; 99(5): 2954-8, 2002 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-11867715

RESUMO

Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Genes APC/fisiologia , Adenoma/genética , Neoplasias Colorretais/genética , Primers do DNA , Éxons , Deleção de Genes , Testes Genéticos/métodos , Humanos , Reação em Cadeia da Polimerase/métodos
13.
Mol Med Today ; 6(12): 462-9, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11099951

RESUMO

Mutations in the adenomatous polyposis coli (APC) gene are the basis of familial adenomatous polyposis and the majority of sporadic colorectal cancer. APC is expressed in a wide variety of tissues, interacts with the cytoskeleton, is involved in regulating levels of beta-catenin and, most recently, has been shown to bind DNA, suggesting that it may possess a nuclear role. The mutation spectrum implicated in tumorigenesis and its correlation with disease phenotype is well characterized and has contributed to our understanding of important functional domains in APC. Despite these advances, APC continues to provide a fertile subject of research for both colorectal tumorigenesis and cancer in general.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Proteínas do Citoesqueleto/metabolismo , Genes APC , Polipose Adenomatosa do Colo/fisiopatologia , Proteína da Polipose Adenomatosa do Colo , Neoplasias Colorretais/fisiopatologia , Humanos , Mutação
14.
Hum Mol Genet ; 9(15): 2215-21, 2000 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-11001924

RESUMO

Mendelian tumour syndromes are caused by rare mutations, which usually lead to protein inactivation. Few studies have determined whether or not the same genes harbour other, more common variants, which might have a lower penetrance and/or cause mild disease, perhaps indistinguishable from sporadic disease and accounting for a considerable proportion of the unexplained inherited risk of tumours in the general population. Germline variants at the APC locus are excellent candidates for explaining why some individuals are predisposed to colorectal adenomas, but do not have the florid phenotype of familial adenomatous polyposis. We have screened 164 unrelated patients with 'multiple' (3-100) colorectal adenomas for germline variants throughout the APC gene, including promoter mutations. In addition to three Ashkenazi patients with I1307K, we found seven patients with the E1317Q variant. E1317Q is significantly associated with multiple colorectal adenomas (OR = 11. 17, 95% CI = 2.30-54.3, p < 0.001), accounting for approximately 4% of all patients with multiple colorectal adenomas. In addition, four patients with truncating APC variants in exon 9 or in the 3' part of the gene were identified. Germline APC variants account for approximately 10% of patients with multiple adenomas. Unidentified predisposition genes almost certainly exist. We argue that it is worthwhile to screen multiple adenoma patients for a restricted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of colorectal tumours, for truncating mutations 5' to exon 5, in exon 9 and 3' to codon 1580.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Genes APC , Mutação em Linhagem Germinativa , Polipose Adenomatosa do Colo/genética , Adolescente , Adulto , Análise Mutacional de DNA , Mutação da Fase de Leitura , Genes Supressores de Tumor , Humanos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Deleção de Sequência
15.
Proc Natl Acad Sci U S A ; 97(7): 3352-7, 2000 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-10737795

RESUMO

Although APC mutations occur at a high frequency in colorectal cancers, few studies have performed a comprehensive analysis by screening the whole gene for mutations and assessing allelic loss. APC seems to act as a tumor-suppressor gene in a "nonclassical" fashion: data from familial adenomatous polyposis (FAP) show that the site of the germ-line mutation determines the type of "second hit" in FAP tumors, and simple protein inactivation is selected weakly, if at all. In this study, we screened the entire coding region of APC for mutations and assessed allelic loss in a set of 41 colorectal cancer cell lines. Of 41 cancers, 32 (83%) showed evidence of APC mutation and/or allelic loss. We identified several APC mutations and found a "hotspot" for somatic mutation in sporadic colorectal tumors at codon 1,554. Our results suggest that APC mutations occur in the great majority of colorectal cancers, the exceptions almost all being RER+ tumors, which may substitute for altered APC function by mutations in beta-catenin and/or at other loci. When combined with previously published data, our results show that there is interdependence of the "two hits" at APC in sporadic colorectal tumors as well as in FAP. APC mutations in the "mutation cluster region," especially those close to codon 1,300, are associated with allelic loss, whereas tumors with mutations outside this region tend to harbor truncating mutations. The causes of this phenomenon are probably selection for retained N-terminal and lost C-terminal APC functions, effects on beta-catenin levels, and APC protein stability.


Assuntos
Neoplasias Colorretais/genética , Genes APC , Mutação , Transativadores , Sequência de Bases , Proteínas do Citoesqueleto/genética , Primers do DNA , Humanos , Perda de Heterozigosidade , Células Tumorais Cultivadas , beta Catenina
16.
Eur J Cancer ; 36(4): 533-4, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10717532

RESUMO

The CAG repeat in exon 1 of the androgen receptor (AR) genes has been postulated as both a susceptibility allele and phenotypic modifier in BRCA1-associated breast cancers. We have analysed this repeat in a set of 178 breast cancer cases who have been selected only for age of presentation at 65 years or less. No effect of repeat length on age of presentation was found and there was no association between repeat length and family history. In combination with the data from other workers, our findings suggest that the androgen receptor repeat does not act as a modifier gene or susceptibility locus outside the context of the hereditary breast/ovarian cancer syndrome.


Assuntos
Neoplasias da Mama/genética , Receptores Androgênicos/genética , Repetições de Trinucleotídeos/genética , Adulto , Idade de Início , Éxons , Feminino , Humanos , Pessoa de Meia-Idade
17.
Proc Natl Acad Sci U S A ; 97(5): 2225-8, 2000 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-10681434

RESUMO

It is not clear whether APC mutations are sufficient for early colorectal adenomas to grow or whether additional mutations at other loci are required. We previously have screened 210 early colorectal adenomas from familial adenomatous polyposis patients for mutations and allelic loss at APC. Here, we determined whether allelic loss at APC had any effect on the nearby alpha-catenin gene. However, loss on 5q in familial adenomatous polyposis adenomas rarely extended as far as alpha-catenin, and no differences in alpha-catenin protein expression were found in tumors that showed loss encompassing both APC and alpha-catenin. We then screened all 210 tumors for mutations at candidate loci other than APC (K-ras, beta-catenin, and allelic loss at 1p33-p35 and 1p36) and for microsatellite instability (MSI). Each of these loci has been implicated previously in early colorectal tumorigenesis. One tumor harbored a beta-catenin mutation and another MSI, but none showed K-ras mutation or allelic loss at 1p33-p35 or 1p36. These data support the following hypotheses derived from sporadic colorectal tumors: beta-catenin mutations are generally an alternative to mutations at APC, MSI is not usually an early phenomenon in colorectal tumorigenesis, and K-ras mutations are more typical of large- and moderate-sized adenomas. Contrary to some previous reports, chromosome 1p allelic loss is infrequent in very early adenomas. APC mutations are generally sufficient for colorectal tumors to grow to about 1-cm diameter, although chance mutations at other loci can provide these early colorectal adenomas with a selective advantage, and some colorectal tumors may develop along a pathway not involving APC.


Assuntos
Adenoma/genética , Polipose Adenomatosa do Colo/genética , Proteínas do Citoesqueleto/genética , Mutação em Linhagem Germinativa , Adenoma/patologia , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo , Humanos
18.
Nat Med ; 5(9): 1071-5, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10470088

RESUMO

APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations. Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1,250-1,450) indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194-1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline-somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Genes APC/genética , Mutação em Linhagem Germinativa/genética , Modelos Genéticos , Mutação/genética , Adenoma/genética , Adenoma/patologia , Polipose Adenomatosa do Colo/patologia , Alelos , Sequência de Bases , Códon/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Éxons/genética , Saúde da Família , Fibromatose Agressiva/genética , Fibromatose Agressiva/patologia , Mutação da Fase de Leitura/genética , Deleção de Genes , Frequência do Gene , Humanos
19.
J Med Genet ; 32(8): 585-9, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7473646

RESUMO

OBJECTIVE: To determine in healthy men: (1) whether an extended genotype of the fibrinogen gene cluster using the G/A-455 and the BclI polymorphism of the beta fibrinogen gene and TaqI of the alpha fibrinogen gene explains a significantly larger proportion of variance in plasma fibrinogen levels in either smokers or non-smokers than a single polymorphism (G/A-455); (2) whether there is any evidence for genotype-smoking interaction in the determination of fibrinogen levels. DESIGN: A cross sectional study of healthy, white men recruited at the screening for entry into the Thrombosis Prevention Trial. SETTING: The subjects were drawn from four general practices in the United Kingdom. RESULTS: The frequency of the rare alleles in the sample was 0.19 for the G/A-455 polymorphism (A-455), 0.15 for BclI (B+), and 0.27 for TaqI (T+) alleles. BMI and age made significant contributions to the variance in plasma fibrinogen levels only in non-smokers of 5.4% and 2.3% respectively and, in the group as a whole, smoking accounted for 6.6% of the variance. In the non-smokers, of the individual polymorphisms only the G/A-455 showed a significant association with plasma fibrinogen levels (p = 0.03). The mean fibrinogen in non-smokers homozygous for the G-455 allele was 2.54 g/l v 2.85 g/l in those homozygous for the A-455 allele, with the polymorphism explaining 3.6% of the variance in plasma fibrinogen levels in this group. On investigation of the association of fibrinogen levels with combined genotypes, the most significant effect was seen with the combination of the G/A-455 and TaqI polymorphisms, with those with no "fibrinogen raising alleles" having a mean fibrinogen of 2.57 g/l v 3.10 g/l for those with four "fibrinogen raising alleles" (p = 0.0036), and this combination explained 8.9% of the variance in plasma fibrinogen levels (p < 0.005). Although the contribution to variance was greater with the G/A-455/TaqI combination than the G/A-455 polymorphism alone (8.9% v 3.6%), this did not reach significance (p = 0.09). By contrast, in the smoking group, the only significant contribution to the difference in plasma fibrinogen levels was the G/A-455 genotype alone which, after adjustment for BMI and age, contributed 3.8% to the variance (p < 0.05). No interaction was shown between smoking and genotype. CONCLUSION: These data suggest that in non-smokers an extended genotype using the G/A-455 beta fibrinogen gene polymorphism and the TaqI alpha fibrinogen gene polymorphism explains a larger proportion of the variance in plasma fibrinogen levels than any one polymorphism alone, but that smoking has an overriding effect so that other variables such as age and BMI make little additional contribution.


Assuntos
Fibrinogênio/genética , Fibrinogênio/metabolismo , Família Multigênica , Polimorfismo Genético , Fumar/sangue , Fumar/genética , Alelos , Variação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Valores de Referência , Análise de Regressão , Mapeamento por Restrição
20.
Ann Hum Genet ; 59(1): 17-24, 1995 01.
Artigo em Inglês | MEDLINE | ID: mdl-7762981

RESUMO

Proteolytic imbalance may play a role in the pathogenesis of abdominal aortic aneurysms (AAA). CLG4B, which encodes the 92-kDa form of type IV collagenase, is a candidate gene for AAA. We genotyped a polymorphic dinucleotide repeat in the 5' flanking region of CLG4B in 94 unrelated Caucasian controls and in 127 unrelated Caucasian AAA cases. Eight alleles were detected in 188 control chromosomes with an observed heterozygosity of 0.68. There was no significant difference in allele distribution between cases and controls. We genotyped the dinucleotide repeat in 10 CEPH reference pedigrees and performed pairwise linkage analysis with markers on each of the 22 human autosomes. Lod scores between 10.45 and 20.29 were observed with markers spanning chromosome region 20q11.2-q13.1. Further support for assignment of CLG4B to chromosome 20 was provided by analysis of human-rodent somatic cell hybrids. This work describes a highly polymorphic marker in the CLG4B gene and assigns this gene to chromosome 20.


Assuntos
Aneurisma Aórtico/genética , Cromossomos Humanos Par 20 , Colagenases/genética , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico , Aneurisma Aórtico/enzimologia , Sequência de Bases , Mapeamento Cromossômico , Colagenases/deficiência , Feminino , Genes , Humanos , Células Híbridas , Masculino , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Linhagem
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