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OBJECTIVE: To determine the quality and effectiveness of national data linkage capacity by performing a proof-of-concept project investigating cross-border hospital use and hospital-related deaths. DESIGN, PARTICIPANTS AND SETTING: Analysis of person-level linked hospital separation and death registration data of all public and private hospital patients in New South Wales, Queensland and Western Australia and of public hospital patients in South Australia, totalling 7.7 million hospital patients from 1 July 2004 to 30 June 2009. MAIN OUTCOME MEASURES: Counts and proportions of hospital stays and patient movement patterns. RESULTS: 223 262 patients (3.0%) travelled across a state border to attend hospitals, in particular, far northern and western NSW patients travelling to Queensland and SA hospitals, respectively. A further 48 575 patients (0.6%) moved their place of residence interstate between hospital visits, particularly to and from areas associated with major mining and tourism industries. Over 11 000 cross-border hospital transfers were also identified. Of patients who travelled across a state border to hospital, 2800 (1.3%) died in that hospital. An additional 496 deaths recorded in one jurisdiction occurred within 30 days of hospital separation from another jurisdiction. CONCLUSIONS: Access to person-level data linked across jurisdictions identified geographical hot spots of cross-border hospital use and hospital-related deaths in Australia. This has implications for planning of health service delivery and for longitudinal follow-up studies, particularly those involving mobile populations.
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Emigração e Imigração , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Hospitais/estatística & dados numéricos , Austrália , Estudos de Coortes , Coleta de Dados , Seguimentos , Humanos , Estudos Retrospectivos , ViagemRESUMO
BACKGROUND: Geocoding, the process of converting textual information describing a location into one or more digital geographic representations, is a routine task performed at large organizations and government agencies across the globe. In a health context, this task is often a fundamental first step performed prior to all operations that take place in a spatially-based health study. As such, the quality of the geocoding system used within these agencies is of paramount concern to the agency (the producer) and researchers or policy-makers who wish to use these data (consumers). However, geocoding systems are continually evolving with new products coming on the market continuously. Agencies must develop and use criteria across a number axes when faced with decisions about building, buying, or maintaining any particular geocoding systems. To date, published criteria have focused on one or more aspects of geocode quality without taking a holistic view of a geocoding system's role within a large organization. The primary purpose of this study is to develop and test an evaluation framework to assist a large organization in determining which geocoding systems will meet its operational needs. METHODS: A geocoding platform evaluation framework is derived through an examination of prior literature on geocoding accuracy. The framework developed extends commonly used geocoding metrics to take into account the specific concerns of large organizations for which geocoding is a fundamental operational capability tightly-knit into its core mission of processing health data records. A case study is performed to evaluate the strengths and weaknesses of five geocoding platforms currently available in the Australian geospatial marketplace. RESULTS: The evaluation framework developed in this research is proven successful in differentiating between key capabilities of geocoding systems that are important in the context of a large organization with significant investments in geocoding resources. Results from the proposed methodology highlight important differences across all axes of geocoding system comparisons including spatial data output accuracy, reference data coverage, system flexibility, the potential for tight integration, and the need for specialized staff and/or development time and funding. Such results can empower decisions-makers within large organizations as they make decisions and investments in geocoding systems.
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Bases de Dados Factuais/normas , Sistemas de Informação Geográfica/normas , Mapeamento Geográfico , Humanos , Austrália Ocidental/epidemiologiaRESUMO
OBJECTIVE: To measure the 'public good' by retrieving, collating, reviewing and assessing outputs from projects using information supplied from the Western Australian Data Linkage System (WADLS) during 1995-2003. METHODS: Using WADLS project application records, all investigators were contacted and requested to submit research outputs for review. RESULTS: 708 outputs comprising journal articles, reports, presentations, conference proceedings, media, theses and other items were reported. During the review, consequential policy reforms in mental health, crystalline silica exposure guidelines and surgical mortality audit were identified. Consequential clinical practice reforms had occurred in laparoscopic, cholecystectomy and acute coronary care. CONCLUSIONS: Data linkage can make a substantial and quantifiable contribution to population health and policy development.
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Política de Saúde , Pesquisa sobre Serviços de Saúde/organização & administração , Informática Médica , Registro Médico Coordenado , Saúde Pública , Coleta de Dados , Medicina Baseada em Evidências , Humanos , Vigilância da População , Projetos de Pesquisa , Austrália OcidentalRESUMO
BACKGROUND: Data linkage is a technique that has long been used to connect information across several disparate data sources--most commonly for medical and population health research. Often the purpose is to connect data for individuals over extended time periods or across different service settings, and so person-based linkage using detailed personal information is preferred. Linkage which aims to link connected events, on the other hand, requires information about the time and place of the event as well as the person or persons involved in that event in order to make high quality linkages. This paper describes the detailed process of event linkage and compares directly an event-based linkage method for identifying transition events between two care sectors in Australia with a well-established high quality longitudinal person-based linkage which facilitates identification of event data for individuals. METHODS: Direct comparisons are made between transition events identified using an event-based linkage and an existing person-based linkage for people moving from hospital into aged care in Western Australia. Several aspects of event-based linkage are examined: refinement of the strategy to reduce false positives, causes of false positives and false negatives, quality of the linked event dataset, and utility of the linked event dataset for transition analysis. RESULTS: Over 97% of the event-based links were among those selected using the person-based linkage and over 90% of the latter were identified by the event-based method, with the remainder missed mostly due to differences in reported event date or residential region. Consequently the two linked datasets were sufficiently similar to give very similar results for analyses, but the actual volume of movement from hospital to RAC was underestimated by about 10% by the event-based method. CONCLUSION: This project has allowed a 'preferred event' event-based linkage strategy to be selected and deployed across Australia to study movements from hospital to residential aged care facilities using databases in which only limited personal information is available, but event dates and details can be readily accessed. The utility of this approach in other transition situations depends on the volume of movement and the accuracy of recording information in each setting.
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Coleta de Dados/métodos , Prestação Integrada de Cuidados de Saúde/organização & administração , Registro Médico Coordenado/métodos , Humanos , Sistemas Computadorizados de Registros Médicos/normas , Alta do Paciente , Integração de Sistemas , Austrália OcidentalRESUMO
OBJECTIVES: The report describes the strategic design, steps to full implementation and outcomes achieved by the Western Australian Data Linkage System (WADLS), instigated in 1995 to link up to 40 years of data from over 30 collections for an historical population of 3.7 million. Staged development has seen its expansion, initially from a linkage key to local health data sets, to encompass links to national and local health and welfare data sets, genealogical links and spatial references for mapping applications. APPLICATIONS: The WADLS has supported over 400 studies with over 250 journal publications and 35 graduate research degrees. Applications have occurred in health services utilisation and outcomes, aetiologic research, disease surveillance and needs analysis, and in methodologic research. BENEFITS: Longitudinal studies have become cheaper and more complete; deletion of duplicate records and correction of data artifacts have enhanced the quality of information assets; data linkage has conserved patient privacy; community machinery necessary for organised responses to health and social problems has been exercised; and the commercial return on research infrastructure investment has exceeded 1000%. Most importantly, there have been unbiased contributions to medical knowledge and identifiable advances in population health arising from the research.
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Registro Médico Coordenado/métodos , Sistemas Computadorizados de Registros Médicos/organização & administração , Bases de Dados Factuais , História do Século XX , História do Século XXI , Humanos , Sistemas Computadorizados de Registros Médicos/história , Vigilância da População , Austrália OcidentalRESUMO
There is growing evidence that common variants of the transforming growth factor-beta (TGF-beta) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-beta signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-beta circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-beta signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-beta signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population.
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Neoplasias da Mama/genética , Fator de Crescimento Transformador beta/genética , Receptores de Ativinas Tipo I/genética , Adulto , Idoso , Alelos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Serina-Treonina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de SinaisRESUMO
BACKGROUND: Hospitals and death registries in Australia are operated under individual state government jurisdictions. Some state borders are located in heavily populated areas or are located near to major capital cities. Mortality indicators for hospital located near state borders may not be estimated accurately if patients are lost as they cross state borders. The aim of this study was to evaluate how cross-jurisdictional linkage of state hospital and death records across state borders may improve estimation of the hospital standardized mortality ratio (HSMR), a tool used in Australia as a hospital performance indicator. METHOD: Retrospective cohort study of 7.7 million hospital patients from July 2004 to June 2009. Inhospital deaths and deaths within 30 days of hospital discharge from four state jurisdictions were used to estimate the standardized mortality ratio of hospital groups defined by geography and type of hospital (grouped HSMR) under three record linkage scenarios, as follows: (1) cross-jurisdictional person-level linkage, (2) within-jurisdictional (state-based) person-level linkage, and (3) unlinked records. All public and private hospitals in New South Wales, Queensland, Western Australia, and public hospitals in South Australia were included in this study. Death registrations from all four states were obtained from state-based registries of births, deaths, and marriages. RESULTS: Cross-jurisdictional linkage identified 11,116 cross-border hospital transfers of which 170 resulted in a cross-border inhospital death. An additional 496 cross-border deaths occurred within 30 days of hospital discharge. The inclusion of cross-jurisdictional person-level links to unlinked hospital records reduced the coefficient of variation among the grouped HSMRs from 0.19 to 0.15; the inclusion of 30-day deaths reduced the coefficient of variation further to 0.11. There were minor changes in grouped HSMRs between cross-jurisdictional and within-jurisdictional linkages, although the impact of cross-jurisdictional linkage increased when restricted to regions with high cross-border hospital use. CONCLUSION: Cross-jurisdictional linkage modified estimates of grouped HSMRs in hospital groups likely to receive a high proportion of cross-border users. Hospital identifiers will be required to confirm whether individual hospital performance indicators change.
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Transcription factor NF-kappaB is constitutively active in many human chronic inflammatory diseases and cancers. Epoxyquinone A monomer (EqM), a synthetic derivative of the natural product epoxyquinol A, has previously been shown to be a potent inhibitor of tumor necrosis factor-alpha (TNF-alpha)-induced activation of NF-kappaB, but the mechanism by which EqM inhibits NF-kappaB activation was not known. In this report, we show that EqM blocks activation of NF-kappaB by inhibiting two molecular targets: IkappaB kinase IKKbeta and NF-kappaB subunit p65. EqM inhibits TNF-alpha-induced IkappaBalpha phosphorylation and degradation by targeting IKKbeta, and an alanine substitution for Cys179 in the activation loop of IKKbeta makes it resistant to EqM-mediated inhibition. EqM also directly inhibits DNA binding by p65, but not p50; moreover, replacement of Cys38 in p65 with Ser abolishes EqM-mediated inhibition of DNA binding. Pretreatment of cells with reducing agent dithiothreitol dose-dependently reduces EqM-mediated inhibition of NF-kappaB, further suggesting that EqM directly modifies the thiol group of Cys residues in protein targets. Modifications of the exocyclic alkene of EqM substantially reduce EqM's ability to inhibit NF-kappaB activation. In the human SUDHL-4 lymphoma cell line, EqM inhibits both proliferation and NF-kappaB DNA binding, and activates caspase-3 activity. EqM also effectively inhibits the growth of human leukemia, kidney, and colon cancer cell lines in the NCI's tumor cell panel. Among six colon cancer cell lines, those with low amounts of constitutive NF-kappaB DNA-binding activity are generally more sensitive to growth inhibition by EqM. Taken together, these results suggest that EqM inhibits growth and induces cell death in tumor cells through a mechanism that involves inhibition of NF-kappaB activity at multiple steps in the signaling pathway.
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Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Cisteína/efeitos dos fármacos , Proteínas I-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinonas/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Camundongos , Mutagênese Sítio-DirigidaRESUMO
OBJECTIVE: To examine the impact of a multi-component health assessment on mortality and morbidity in Kimberley Aboriginal residents during a 13-year follow-up. METHOD: A population-based randomised controlled trial using linked hospital, cancer and death records to evaluate outcomes in 620 intervention and 6,736 control subjects. RESULTS: The intervention group had a higher rate of first-time hospitalisation for any reason (IRR=1.37; 95% CI 1.25-1.50), a higher rate of injury-related hospital episodes (IRR=1.31; 95% CI 1.15-1.48) and a higher notification rate of alcohol-related cancers. There was a smaller difference in the rates of multiple hospitalisations (IRR=1.14; 95% CI 0.75-1.74) and no improvement in overall mortality compared with controls (IRR=1.08; 95% CI 0.91-1.29). CONCLUSIONS: There was no overall mortality benefit despite increased health service contact associated with the intervention. IMPLICATIONS: Although not influencing mortality rates, multi-component health assessment may result in a period of increased health service use in Aboriginal and Torres Strait Islander populations, thus constituting an 'intervention'. However, this should not be confused with systematic and sustained interventions and investment in community development to achieve better health outcomes.
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Indicadores Básicos de Saúde , Hospitalização/estatística & dados numéricos , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Neoplasias/etnologia , Resultado do Tratamento , Ferimentos e Lesões/etnologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/etnologia , Feminino , Seguimentos , Humanos , Masculino , Registro Médico Coordenado , Pessoa de Meia-Idade , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Modelos de Riscos Proporcionais , Sistema de Registros , Austrália Ocidental/epidemiologia , Ferimentos e Lesões/epidemiologiaRESUMO
CONTEXT: TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. OBJECTIVES: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. DESIGN, SETTING, AND PATIENTS: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. MAIN OUTCOME MEASURES: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation. RESULTS: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. CONCLUSIONS: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.
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Receptores de Ativinas Tipo I/genética , Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Neoplasias de Cabeça e Pescoço/genética , Polimorfismo Genético , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais , Alelos , Sequência de Aminoácidos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Neoplásica/genética , Fenótipo , Proteínas Serina-Treonina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo I , Deleção de Sequência , Fator de Crescimento Transformador beta/fisiologiaRESUMO
Prostate cancer is the most commonly diagnosed cancer in men and one of the leading causes of cancer deaths. There is strong genetic evidence indicating that a large proportion of prostate cancers are caused by heritable factors but the search for prostate cancer susceptibility genes has thus far remained elusive. TGFBR1*6A, a common hypomorphic variant of the type I Transforming Growth Factor Beta receptor, is emerging as a tumor susceptibility allele that predisposes to the development of breast, colon and ovarian cancer. The association with prostate cancer has not yet been explored. A total of 907 cases and controls from New York City were genotyped to test the hypothesis that TGFBR1*6A may contribute to the development of prostate cancer. TGFBR1*6A allelic frequency among cases (0.086) was slightly higher than among controls (0.080) but the differences in TGFBR1*6A genotype distribution between cases and controls did not reach statistical significance (p = 0.67). Our data suggest that TGFBR1*6A does not contribute to the development of prostate cancer.
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Receptores de Ativinas Tipo I/genética , Alelos , Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo IRESUMO
BACKGROUND: In the absence in the major Australian administrative health record collections of a direct measure of the socioeconomic status of the individual about whom the event is recorded, analysis of the association between the health status, use of health services and socioeconomic status of the population relies an area-based measure of socioeconomic status.This paper explores the reliability of the area of address (at the levels typically available in administrative data collections) as a proxy measure for socioeconomic disadvantage. The Western Australian Data Linkage System was used to show the extent to which hospital inpatient separation rates for residents of Perth vary by socioeconomic status of area of residence, when calculated at various levels of aggregation of area, from smallest (Census Collection District) to largest (postcode areas and Statistical Local Areas). Results are also provided of the reliability, over time, of the address as a measure of socioeconomic status. RESULTS: There is a strong association between the socioeconomic status of the usual address of hospital inpatients at the smallest level in Perth, and weaker associations when the data are aggregated to larger areas. The analysis also shows that a higher proportion of people from the most disadvantaged areas are admitted to hospital than from the most well-off areas (13% more), and that these areas have more separations overall (47% more), as a result of larger numbers of multiple admissions.Of people admitted to hospital more than once in a five year period, four out of five had not moved address by the time of their second episode. Of those who moved, the most movement was within, or between, areas of similar socioeconomic status, with people from the most well off areas being the least likely to have moved. CONCLUSION: Postcode level and SLA level data provide a reliable, although understated, indication of socioeconomic disadvantage of area. The majority of Perth residents admitted to hospital in Western Australia had the same address when admitted again within five years. Of those who moved address, the majority had moved within, or between, areas of similar socioeconomic status.Access to data about individuals from the Western Australian Data Linkage System shows that more people from disadvantaged areas are admitted to a hospital, and that they have more episodes of hospitalisation. Were data to be available across Australia on a similar basis, it would be possible to undertake research of greater policy-relevance than is currently possible with the existing separations-based national database.
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Transforming growth factor-beta (TGF-beta) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of Tgfbr1 crossed with Apc(Min/+) mice, we show that Apc(Min/+);Tgfbr1(+/-) mice develop twice as many intestinal tumors as Apc(Min/+);Tgfbr1(+/+) mice, as well as adenocarcinoma of the colon, without loss of heterozygosity at the Tgfbr1 locus. Decreased Smad2 and Smad3 phosphorylation and increased cellular proliferation are observed in the colonic epithelium crypts of Apc(Min/+); Tgfbr1(+/-) mice. Smad-mediated TGF-beta signaling is preserved in both Apc(Min/+);Tgfbr1(+/+) and Apc(Min/+);Tgfbr1(+/-) intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in Apc(Min/+);Tgfbr1(+/-) tumors. These results show that constitutively reduced Tgfbr1-mediated TGF-beta signaling significantly enhances colorectal cancer development and results in increased tumor cell proliferation. These findings provide a plausible molecular mechanism for colorectal cancer development in individuals with constitutively altered TGFBR1 expression, a recently identified common form of human colorectal cancer.
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Neoplasias Colorretais/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Animais , Processos de Crescimento Celular/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Hematopoese , Endogamia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/biossíntese , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
TGFBR1*6A is a common hypomorphic variant of the type 1 transforming growth factor beta receptor (TGFBR1), which has been associated with increased cancer risk in some studies. Although TGFBR1*6A is capable of switching TGF-beta growth-inhibitory signals into growth-stimulatory signals when stably transfected into MCF-7 breast cancer cells, the biological effects of TGFBR1*6A are largely unknown. To broadly explore the potential oncogenic properties of TGFBR1*6A, we assessed its effects on NIH-3T3 cells as well as its effect on the migration and invasion of MCF-7 cells. We found that TGFBR1*6A has decreased oncogenic properties compared with TGFBR1. However, TGFBR1*6A significantly enhances MCF-7 cell migration and invasion in a TGF-beta signaling-independent manner. Gene expression profiling studies identified two down-regulated genes involved in cell migration and invasion: ARHGAP5, encoding ARHGAP5, and FN1, encoding fibronectin-1 (FN1). ARHGAP5 and FN1 expression was similarly down-regulated in MCF-7 cells stably transfected with a kinase-inactivated TGFBR1*6A construct. Functional assays show that TGFBR1*6A-mediated decreased ARHGAP5 expression is associated with higher RhoA activation, a crucial mediator of cell migration. Extracellular signal-regulated kinase (ERK) activation is also higher in cells that harbor the TGFBR1*6A allele. We conclude that TGFBR1*6A is not an oncogene but enhances MCF-7 cell migration and invasion through RhoA and ERK pathway activation and down-regulates two crucial mediators of this phenotype. These results provide the first evidence that TGFBR1*6A may contribute to cancer progression in a TGF-beta signaling-independent manner.
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Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteína rhoA de Ligação ao GTP/fisiologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Camundongos , Células NIH 3T3 , Invasividade Neoplásica , Proteínas Serina-Treonina Quinases/fisiologia , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/fisiologia , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
OPINION STATEMENT: The combined observation that 20-30% of all patients with breast cancer have a family history of the disease and the results from twin studies showing that 25% of breast cancer cases are heritable, indicate that this malignancy is one of the most commonly inherited cancers. Discovery of the BRCA1 and BRCA2 genes more than a decade ago has had a tremendous impact on patient care allowing for early detection and prevention of breast cancer. However, deleterious mutations within the BRCA1 and BRCA2 genes cause at most 3-8% of all breast cancer cases. New data indicate that genomic rearrangements within the same genes may occasionally identify additional carriers of nonfunctional BRCA1 and BRCA2 genes. Such genomic rearrangements are missed by conventional sequencing. The remainder of the unexplained familial risk is presumably due to other yet unidentified high penetrance genes, but polygenic mechanisms and high frequency low penetrance tumor susceptibility genes are likely to account for a greater proportion of familial breast cancers. In this regard, there is growing evidence that a common variant of the type I TGF-ss receptor, TGFBR1*6A, may account for approximately 5% of all breast cancer cases, a fraction similar to that attributable to BRCA1 and BRCA2. Such genes may also modify the penetrance of the BRCA1 and BRCA2 genes. In the next decade, screening for combinations of high and low penetrance genes will likely permit the identification of a large fraction of inherited breast cancer cases and will further reduce the burden of familial breast cancer.