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PURPOSE: Globally, lung cancer is the most common cancer and the leading cause of cancer death. Problematically, there is a wide variation in the management and survival for people with lung cancer and there is limited understanding of the reasons for these variations. To date, the views of health professionals across relevant disciplines who deliver such care are largely absent. The present study describes Australian health professionals' views about barriers to lung cancer care to help build a research and action agenda for improving lung cancer outcomes. METHODS: Qualitative semi-structured interviews were undertaken with a multidisciplinary group of 31 Australian health professionals working in lung cancer care for an average of 16 years (range 1-35 yrs.; SD = 10.2) seeing a mean of 116 patients annually. RESULTS: Three superordinate themes were identified: illness representations, cultural influences, and health system context. Illness representations included three themes: symptoms attributed as smoking-related but not cancer, health-related stigma, and therapeutic nihilism. Cultural influence themes included Indigenous health care preferences, language and communication, and sociodemographic factors. Health system context included lack of regional services and distance to treatment, poor care coordination, lack of effective screening methods, and health professional behaviours. CONCLUSIONS: Fractured and locally isolated approaches routinely confound responses to the social, cultural and health system complexities that surround a diagnosis of lung cancer and subsequent treatment. Improving outcomes for this disadvantaged patient group will require government, health agencies, and the community to take an aggressive, integrated approach balancing health policy, treatment priorities, and societal values.
Assuntos
Atitude do Pessoal de Saúde , Acessibilidade aos Serviços de Saúde , Neoplasias Pulmonares/terapia , Austrália , Atenção à Saúde , Feminino , Pessoal de Saúde , Humanos , Masculino , Pesquisa Qualitativa , Estigma Social , Populações VulneráveisRESUMO
BACKGROUND: Lung cancer incidence, mortality and hospitalisation rates are higher for Indigenous Australians compared with non-Indigenous Australians and increase again when living in more remote areas. If Indigenous Australians are made more aware of lung cancer through better access to health services and programmes, lung cancer outcomes might improve. AIM: We aimed to survey the level of lung cancer awareness in rural and remote Aboriginal and Torres Strait Islander communities and discover perceived barriers to timely diagnosis and treatment of lung cancer. METHODS: Interviews were conducted in three discrete outer regional and remote Aboriginal communities and one urban setting in Queensland. Participants included Aboriginal and Torres Strait Islander peoples from three target population groups: patients referred for medical treatment with symptoms suspicious of lung cancer or confirmed lung cancer; Indigenous health workers; community members aged 18 years and over. Participants gave written, informed consent. RESULTS: Of 51 community members and 14 Indigenous health workers, 32 reflected they knew very little about lung cancer, 60 cited smoking as the cause of lung cancer and 54 recognised warning symptoms as a prompt to seek healthcare. Indigenous health workers were not able to describe a healthcare pathway that would apply to a patient with suspected lung cancer. CONCLUSION: The two main barriers identified as impacting on quality healthcare were communication and follow-up processes. These could be addressed by service improvement activities.
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Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/terapia , Havaiano Nativo ou Outro Ilhéu do Pacífico/etnologia , População Rural , Inquéritos e Questionários , Adulto , Feminino , Necessidades e Demandas de Serviços de Saúde , Serviços de Saúde do Indígena , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Queensland/etnologia , Características de Residência , Resultado do TratamentoRESUMO
The traditional roles of Australian cancer registries have been incidence, mortality and survival surveillance although increasingly, roles are being broadened to include data support for health-service management and evaluation. In some Australian jurisdictions, cancer stage and other prognostic data are being included in registry databases and this is being facilitated by an increase in structured pathology reporting by pathology and haematology laboratories. Data linkage facilities are being extended across the country at national and jurisdictional level, facilitating data linkage between registry data and data extracts from administrative databases that include treatment, screening and vaccination data, and self-reported data from large population cohorts. Well-established linkage protocols exist to protect privacy. The aim is to gain better data on patterns of care, service outcomes and related performance indicators for health-service management and population health and health-services research, at a time of increasing cost pressures. Barriers include wariness among some data custodians towards releasing data and the need for clearance for data release from large numbers of research ethics committees. Progress is being made though, and proof of concept is being established.
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Atenção à Saúde/organização & administração , Pesquisa sobre Serviços de Saúde/organização & administração , Registro Médico Coordenado , Neoplasias/terapia , Sistema de Registros , Austrália , Bases de Dados Factuais , Medicina Baseada em Evidências , HumanosRESUMO
BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in Australia. Screening using low-dose computed tomography (LDCT) can reduce lung cancer mortality. The feasibility of screening in Australia is unknown. This paper describes the rationale, design and methods of the Queensland Lung Cancer Screening Study. AIMS: The aim of the study is to describe the methodology for a feasibility study of lung cancer screening by LDCT in Australia. METHODS: The Queensland Lung Cancer Screening Study is an ongoing, prospective observational study of screening by LDCT at a single tertiary institution. Healthy volunteers at high risk of lung cancer (age 60-74 years; smoking history ≥30 pack years, current or quit within 15 years; forced expiratory volume in 1s ≥50% predicted) are recruited from the general public through newspaper advertisement and press release. Participants receive a LDCT scan of the chest at baseline, year 1 and year 2 using a multidetector helical computed tomography scanner and are followed up for a total of 5 years. Feasibility of screening will be assessed by cancer detection rates, lung nodule prevalence, optimal management strategies for lung nodules, economic costs, healthcare utilisation and participant quality of life. CONCLUSIONS: Studying LDCT screening in the Australian setting will help us understand how differences in populations, background diseases and healthcare structures modulate screening effectiveness. This information, together with results from overseas randomised studies, will inform and facilitate local policymaking.
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Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/epidemiologia , Tomografia Computadorizada por Raios X/métodos , Idoso , Detecção Precoce de Câncer/normas , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Queensland/epidemiologia , Fatores de Risco , Tomografia Computadorizada por Raios X/normasRESUMO
The clinical applicability of screening surgically resected nonsmall cell lung cancer (NSCLC) tumour tissue and serum for activating epidermal growth factor receptor (EGFR) mutation is unknown. Furthermore, the comparative accuracy of inexpensive EGFR mutation tests, mutant-enriched (ME)-PCR and high-resolution melt (HRM) has not been determined. Lung tumour DNA from 522 surgically resected stage I-IV NSCLC and matched serum DNA from a subset of 64 subjects was analysed for EGFR mutations in exons 19 and 21 using ME-PCR and HRM. Additionally, 97 subjects had previous EGFR DNA sequencing data available for comparison. ME-PCR and HRM detected EGFR mutations in 5% (27 out of 522) of tumour samples. Compared to DNA sequencing, ME-PCR had a sensitivity of 100% and specificity of 99%, while HRM had 100% sensitivity and specificity. Six subjects with EGFR mutation tumours had matched serum, where ME-PCR detected mutations in three samples and HRM in two samples. In the cohort of never-smoker subjects, those with EGFR mutated tumours had worse survival compared with wild-type tumours (30 versus 49 months; p=0.017). ME-PCR and HRM have similar accuracy in detecting EGFR mutations but the prognostic implications of the mutations in resected NSCLC warrants further study.
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Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Receptores ErbB/genética , Testes Genéticos/métodos , Testes Genéticos/normas , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Éxons/genética , Feminino , Secções Congeladas , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Temperatura de TransiçãoRESUMO
Lung cancer remains a leading cause of disease globally, with smoking being the largest single cause. Phase I enzymes, including cytochrome P(450), family 1, subfamily A, polypeptide 1 (CYP1A1), are involved in the activation of carcinogens, such as polycyclic aromatic hydrocarbons, to reactive intermediates that are capable of binding covalently to DNA to form DNA adducts, potentially initiating the carcinogenic process. The aim of the present study was to investigate the association of CYP1A1 gene polymorphisms and haplotypes with lung cancer risk. A case-control study was carried out on 1,040 nonsmall cell lung cancer (NSCLC) cases and 784 controls to investigate three CYP1A1 variants, CYP1A1*2A (rs4646903; thymidine to cytosine substitution at nucleotide 3801 (3801T>C)), CYP1A1*2C (rs1048943; 2455A>G; substitution of isoleucine 462 with valine (exon 7)) and CYP1A1*4 (rs1799814; 2453C>A; substitution of threonine 461 with asparagine (exon 7)) using PCR restriction fragment length polymorphism methods. The CYP1A1*2A and CYP1A1*2C variants were significantly over-represented in NSCLC cases compared with controls, whereas the CYP1A1*4 variant was under-represented. CYP1A1 haplotypes (in allele order CYP1A1*4, CYP1A1*2C, CYP1A1*2A) CGC and CGT were associated with an increased risk of lung cancer, whereas AAT was associated with decreased lung cancer risk in this population. The present study has identified risk haplotypes for CYP1A1 in NSCLC and confirmed that CYP1A1 polymorphisms are a minor risk factor for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/genética , Citocromo P-450 CYP1A1/genética , Estudos de Associação Genética , Haplótipos/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
AIMS: To determine whether in-hospital deaths of patients admitted through emergency departments with acute exacerbations of chronic obstructive pulmonary disease (COPD), acute myocardial infarction, intracerebral haemorrhage and acute hip fracture are increased by weekend versus weekday admission (the 'weekend effect'). METHODS: We performed a retrospective analysis of statewide administrative data from public hospitals in Queensland, Australia, during the 2002/2003-2006/2007 financial years. The primary outcome was 30-day in-hospital mortality. The secondary outcome of 2-day in-hospital mortality helped determine whether increased mortality of weekend admissions was closely linked to weekend medical care. RESULTS: During the study period, there were 30 522 COPD, 17 910 acute myocardial infarction, 4183 acute hip fracture and 1781 intracerebral haemorrhage admissions. There was no significant weekend effect on 30-day in-hospital mortality for COPD (adjusted risk ratio = 0.92, 95% CI: 0.81-1.04, P= 0.222), intracerebral haemorrhage (adjusted risk ratio = 1.01, 95% CI: 0.86-1.16, P= 0.935) or acute hip fracture (adjusted risk ratio = 0.78, 95% CI: 0.54-1.03, P= 0.13). There was a significant weekend effect for acute myocardial infarction (adjusted risk ratio = 1.15, 95% CI: 1.03-1.26, P= 0.007). Two-day in-hospital mortality showed similar results. CONCLUSION: This is the first Australian study on the 'weekend effect' (in a cohort other than neonates), and the first study worldwide to assess specifically the weekend effect among COPD patients. Observed patterns were consistent with overseas research. There was a significant weekend effect for myocardial infarction. Further research is needed to determine whether location (e.g. rural), clinical (e.g. disease severity) and service provision factors (e.g. access to invasive procedures) influence the weekend effect for acute medical conditions in Australia.
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Mortalidade Hospitalar/tendências , Hospitais Públicos/normas , Hospitais Públicos/tendências , Admissão do Paciente/normas , Admissão do Paciente/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Bases de Dados Factuais/tendências , Feminino , Hospitais Públicos/métodos , Humanos , Masculino , Queensland/epidemiologia , Estudos Retrospectivos , Fatores de TempoRESUMO
There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).
RESUMO
There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).
Assuntos
Poluição do Ar/efeitos adversos , Predisposição Genética para Doença/genética , Pneumopatias/genética , Transtornos Respiratórios/genética , Variação Genética , Humanos , Pneumopatias/induzido quimicamente , Dióxido de Nitrogênio/toxicidade , Ozônio/toxicidade , Material Particulado/toxicidade , Fenótipo , Polimorfismo Genético , Transtornos Respiratórios/induzido quimicamente , Dióxido de Enxofre/toxicidadeRESUMO
BACKGROUND: In several countries, clinical practice guidelines for lung cancer recommend that multidisciplinary (MD) teams should be used to plan the management of all lung cancer patients. We conducted a systematic review to evaluate and critically appraise the effectiveness of multidisciplinary teams for lung cancer. MATERIALS AND METHODS: Medline searches were carried out for the period 1984 to July 2007. We included any study that mentioned team working among specialists with diagnostic and curative therapeutic intent, where members of the team met at a specified time, either in person or by video or teleconferencing, to discuss the diagnosis and management of patients with suspected lung cancer. All study designs were included. We were particularly interested in whether multidisciplinary working improved survival but also considered other outcomes such as practice patterns and waiting times. RESULTS: Sixteen studies met the criteria for inclusion. Statistical pooling was not possible due to clinical heterogeneity. Only two of the primary studies reported an improvement in survival. Both were before-and-after designs, providing weak evidence of a causal association. Evidence of the effect of MD teams was stronger for changing patient management than for affecting survival. Six of the studies reported an increase in the percentage of patients undergoing surgical resection or an increase in the percentage of patients undergoing chemotherapy or radiotherapy with curative intent. CONCLUSION: This systematic review shows limited evidence linking MD teams with improved lung cancer survival. This does not mean that MD teams do not improve survival, merely that currently available evidence of this is limited. It seems intuitively obvious that MD teams should improve outcomes for lung cancer patients, but there are difficulties in conducting randomised trials to show this. The best way forward would be prospective evaluation of the effectiveness of MD teams as they are implemented, paying particular attention to collecting data on potential confounders.
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Neoplasias Pulmonares/terapia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/psicologia , Satisfação do Paciente , Padrões de Prática Médica , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) has been the subject of much controversy. Major international guidelines recommend selective use of ICS. Recently published meta-analyses have reported conflicting findings on the effects of inhaled steroid therapy in COPD. OBJECTIVES: The objective of the review is to determine the efficacy of regular use of inhaled corticosteroids in patients with stable COPD. SEARCH STRATEGY: A pre-defined search strategy was used to search the Cochrane Airways Group specialised register for relevant literature. Searches are current as of October 2006. SELECTION CRITERIA: We selected randomised trials comparing any dose of any type of inhaled steroid with a placebo control in patients with COPD. Acute bronchodilator reversibility to short term beta2-agonists and bronchial hyperresponsiveness were not exclusion criteria. The a priori primary outcome was change in lung function. Data on mortality, exacerbations, quality of life and symptoms, rescue bronchodilator use, exercise capacity, biomarkers and safety were also analysed. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Forty-seven primary studies with 13,139 participants met the inclusion criteria. Medium term use of ICS (> two months and up to six months) resulted in a small improvement in FEV1 in some studies. Long term use of ICS (> six months) did not significantly reduce the rate of decline in FEV1 in COPD patients (weighted mean difference (WMD) 5.80 ml/year with ICS over placebo, 95% CI -0.28 to 11.88, 2333 participants). There was no statistically significant effect on mortality in COPD patients (OR 0.98, 95% CI 0.83 to 1.16, 8390 participants). Long term use of ICS reduced the mean rate of exacerbations in those studies where pooling of data was possible (WMD -0.26 exacerbations per patient per year, 95% CI -0.37 to -0.14, 2586 participants). ICS slowed the rate of decline in quality of life, as measured by the St George's Respiratory Questionnaire (WMD -1.22 units/year, 95% CI -1.83 to -0.60, 2507 participants). Response to ICS was not predicted by oral steroid response, bronchodilator reversibility or bronchial hyper-responsiveness in COPD patients. There was an increased risk of oropharyngeal candidiasis (OR 2.49, 95% CI 1.78 to 3.49, 4380 participants) and hoarseness. The few long term studies that measured bone effects generally showed no major effect on fractures and bone mineral density over 3 years. AUTHORS' CONCLUSIONS: Patients and clinicians should balance the potential benefits of inhaled steroids in COPD (reduced rate of exacerbations, reduced rate of decline in quality of life), against the known increase in local side effects (oropharyngeal candidiasis and hoarseness). The risk of long term adverse effects is unknown.
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Corticosteroides/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Corticosteroides/efeitos adversos , Hiper-Reatividade Brônquica/tratamento farmacológico , Broncodilatadores/efeitos adversos , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Chromosome 3p14.2 contains FRA3B, the most active chromosome breakage site in the human genome. The fragile histidine triad (FHIT) gene, a putative tumor suppressor gene, overlaps FRA3B. Human papillomavirus (HPV), a known cofactor in cervical carcinogenesis, can integrate into FRA3B. We examined abnormalities in FHIT and its RNA transcripts in cervical cancer cell lines and tumors. We also investigated the relationship between loss of heterozygosity (LOH) in FHIT/FRA3B and the presence of oncogenic HPV types. METHODS: Eleven cell lines, 40 tumors (20 fresh and 20 archival), and 10 normal cervical epithelia were examined. Two intragenic polymorphic markers (D3S1300 and D3S4103) and the polymerase chain reaction (PCR) were used to examine FHIT LOH. Reverse transcription-PCR (RT-PCR) analysis and single-strand conformation polymorphism analysis of RT-PCR products were used to characterize FHIT transcripts. Oncogenic HPV types were identified by PCR, using general and type-specific primers. RESULTS: All normal epithelia, 19 of 20 fresh tumors and nine of 11 cell lines expressed wild-type and, occasionally, exon 8-deleted FHIT transcripts. Additional aberrant FHIT transcripts were seen in nine of 20 fresh tumors and in seven of 11 cell lines. DNA sequencing of the aberrant transcripts revealed a variety of insertions and deletions but no point mutations. Three cell lines also had homozygous FHIT deletions. Oncogenic HPV types (i.e., 16, 18, 31, and 33) were detected in 18 of 20 archival tumors, and, in these tumors, LOH within FHIT was identified in nine of 16 informative cases. HPV 16 was found to be associated with LOH in the FHIT/FRA3B region (P = .041). CONCLUSION: FHIT/FRA3B is frequently altered in cervical cancer, demonstrating LOH, occasional homozygous deletions, and frequent aberrant transcripts not found in normal epithelia. However, the presence of wild-type transcripts and the lack of protein-altering point mutations raise questions about FHIT's function as a classic tumor suppressor gene in cervical tissue.
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Deleção Cromossômica , Fragilidade Cromossômica , Cromossomos Humanos Par 3/genética , DNA Complementar/genética , DNA de Neoplasias/genética , Infecções por Papillomavirus/complicações , Infecções Tumorais por Vírus/complicações , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Feminino , Heterozigoto , Humanos , Papillomaviridae , Reação em Cadeia da Polimerase/métodos , Polimorfismo Conformacional de Fita Simples , Transcrição Gênica , Células Tumorais CultivadasRESUMO
BACKGROUND: Most lung cancers are attributed to smoking. These cancers have been associated with multiple genetic alterations and with the presence of preneoplastic bronchial lesions. In view of such associations, we evaluated the status of specific chromosomal loci in histologically normal and abnormal bronchial biopsy specimens from current and former smokers and specimens from nonsmokers. METHODS: Multiple biopsy specimens were obtained from 18 current smokers, 24 former smokers, and 21 nonsmokers. Polymerase chain reaction-based assays involving 15 polymorphic microsatellite DNA markers were used to examine eight chromosomal regions for genetic changes (loss of heterozygosity [LOH] and microsatellite alterations). RESULTS: LOH and microsatellite alterations were observed in biopsy specimens from both current and former smokers, but no statistically significant differences were observed between the two groups. Among individuals with a history of smoking, 86% demonstrated LOH in one or more biopsy specimens, and 24% showed LOH in all biopsy specimens. About half of the histologically normal specimens from smokers showed LOH, but the frequency of LOH and the severity of histologic change did not correspond until the carcinoma in situ stage. A subset of biopsy specimens from smokers that exhibited either normal or preneoplastic histology showed LOH at multiple chromosomal sites, a phenomenon frequently observed in carcinoma in situ and invasive cancer. LOH on chromosomes 3p and 9p was more frequent than LOH on chromosomes 5q, 17p (17p13; TP53 gene), and 13q (13q14; retinoblastoma gene). Microsatellite alterations were detected in 64% of the smokers. No genetic alterations were detected in nonsmokers. CONCLUSIONS: Genetic changes similar to those found in lung cancers can be detected in the nonmalignant bronchial epithelium of current and former smokers and may persist for many years after smoking cessation.
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Brônquios/metabolismo , Deleção Cromossômica , Dano ao DNA , Fumar/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Autorradiografia , Brônquios/patologia , Epitélio/metabolismo , Epitélio/patologia , Feminino , Heterozigoto , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Abandono do Hábito de Fumar , Fatores de TempoRESUMO
BACKGROUND: Retinoic acid plays an important role in lung development and differentiation, acting primarily via nuclear receptors encoded by the retinoic acid receptor-beta (RARbeta) gene. Because receptor isoforms RARbeta2 and RARbeta4 are repressed in human lung cancers, we investigated whether methylation of their promoter, P2, might lead to silencing of the RARbeta gene in human lung tumors and cell lines. METHODS: Methylation of the P2 promoter from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines and tumor samples was analyzed by the methylation-specific polymerase chain reaction (PCR). Expression of RARbeta2 and RARbeta4 was analyzed by reverse transcription-PCR. Loss of heterozygosity (LOH) was analyzed by PCR amplification followed by electrophoretic separation of PCR products. Statistical differences were analyzed by Fisher's exact test with continuity correction. RESULTS: The P2 promoter was methylated in 72% (63 of 87) of SCLC and in 41% (52 of 127) of NSCLC tumors and cell lines, and the difference was statistically significant (two-sided P:<.001). By contrast, in 57 of 58 control samples, we observed only the unmethylated form of the gene. Four tumor cell lines with unmethylated promoter regions expressed both RARbeta2 and RARbeta4. Four tumor lines with methylated promoter regions lacked expression of these isoforms, but demethylation by exposure to 5-aza-2'-deoxycytidine restored their expression. LOH at chromosome 3p24 was observed in 100% (13 of 13) of SCLC lines and 67% (12 of 18) of NSCLC cell lines, and the difference was statistically significant (two-sided P: =.028). CONCLUSIONS: Methylation of the RARbeta P2 promoter is one mechanism that silences RARbeta2 and RARbeta4 expression in many lung cancers, particularly SCLC. Chemical demethylation is a potential approach to lung cancer therapy.
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Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Pequenas/metabolismo , Perda de Heterozigosidade , Neoplasias Pulmonares/metabolismo , Regiões Promotoras Genéticas , Receptores do Ácido Retinoico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Metilação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
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.
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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-IdadeRESUMO
Microsatellites are highly polymorphic, short-tandem repeat sequences dispersed throughout the genome. Instability of these repeat sequences at multiple genetic loci may result from mismatch repair errors and occur in hereditary nonpolyposis colorectal carcinoma and certain sporadic cancers. In non-small cell lung cancer, we found that microsatellite instability was infrequent, affecting only 7 (6.5%) of 108 cases. Despite being observed in all histological subtypes and at different tumor stages, microsatellite instability most commonly affected only one of the six loci tested on five chromosomal arms. In addition, microsatellite instability was associated with extensive, concurrent molecular changes including K-ras and p53 mutations as well as frequent loss of heterozygosity at chromosomal regions 5q, 8p, 9p, 11p, and 17p.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Satélite , Neoplasias Pulmonares/genética , Mutação , Idoso , Sequência de Bases , Deleção Cromossômica , Feminino , Genes p53 , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência MolecularRESUMO
Aberrant methylation of CpG islands acquired in tumor cells in promoter regions is one method for loss of gene function. We determined the frequency of aberrant promoter methylation (referred to as methylation) of the genes retinoic acid receptor beta-2 (RARbeta), tissue inhibitor of metalloproteinase 3 (TIMP-3), p16INK4a, O6-methylguanine-DNA-methyltransferase (MGMT), death-associated protein kinase (DAPK), E-cadherin (ECAD), p14ARF, and glutathione S-transferase P1 (GSTP1) in 107 resected primary non-small cell lung cancers (NSCLCs) and in 104 corresponding nonmalignant lung tissues by methylation-specific PCR. Methylation in the tumor samples was detected in 40% for RARbeta, 26% for TIMP-3, 25% for p16INK4a, 21% for MGMT, 19% for DAPK, 18% for ECAD, 8% for p14ARF, and 7% for GSTP1, whereas it was not seen in the vast majority of the corresponding nonmalignant tissues. Moreover, p16INK4a methylation was correlated with loss of p16INK4a expression by immunohistochemistry. A total of 82% of the NSCLCs had methylation of at least one of these genes; 37% of the NSCLCs had one gene methylated, 22% of the NSCLCs had two genes methylated, 13% of the NSCLCs had three genes methylated, 8% of the NSCLCs had four genes methylated, and 2% of the NSCLCs had five genes methylated. Methylation of these genes was correlated with some clinicopathological characteristics of the patients. In comparing the methylation patterns of tumors and nonmalignant lung tissues from the same patients, there were many discordancies where the genes methylated in nonmalignant tissues were not methylated in the corresponding tumors. This suggests that the methylation was occurring as a preneoplastic change. We conclude that these findings confirm in a large sample that methylation is a frequent event in NSCLC, can also occur in smoking-damaged nonmalignant lung tissues, and may be the most common mechanism to inactivate cancer-related genes in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Neoplasias Pulmonares/genética , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose , Caderinas/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Proteínas Quinases Associadas com Morte Celular , Feminino , Genes p16/genética , Glutationa S-Transferase pi , Glutationa Transferase/genética , Humanos , Imuno-Histoquímica , Isoenzimas/genética , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , O(6)-Metilguanina-DNA Metiltransferase/genética , Reação em Cadeia da Polimerase/métodos , Proteínas/genética , Receptores do Ácido Retinoico/genética , Fatores de Risco , Taxa de Sobrevida , Inibidor Tecidual de Metaloproteinase-3/genética , Proteína Supressora de Tumor p14ARFRESUMO
Although the short arm of chromosome 17, which contains the p53 gene, is frequently affected by loss of heterozygosity (LOH) in lung cancer, little is known about similar changes on the long arm. We found that LOH affected one or more of six loci along chromosome 17 in 59% of 102 informative non-small cell lung cancer (NSCLC) cases. Specifically, the frequency of LOH at 17q was 42%, approaching that at 17p (54%), and two distinct 17q regions were implicated. LOH at D17S4 on 17q was more frequent in adenocarcinomas than in squamous cell carcinomas, whereas squamous cell carcinomas had more LOH at 17p than at 17q, findings that indicate molecular genetic heterogeneity between the major NSCLC subtypes. In addition, LOH at 17q correlated with higher T stages and a significantly worse prognosis. In comparison, 25% of cases had mutations of p53 exons 5-8 but these were not associated with stage or survival. The data suggest that independent of p53, there are important tumor suppressor gene(s) on 17q that may influence NSCLC pathogenesis, progression, and survival.