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1.
Cell ; 173(3): 581-594.e12, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29656895

RESUMO

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação , Metástase Neoplásica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Mapeamento Cromossômico , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 9 , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Trombose , Resultado do Tratamento
2.
Nature ; 616(7957): 534-542, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37046095

RESUMO

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Evolução Clonal , Células Clonais , Evolução Molecular , Neoplasias Pulmonares , Metástase Neoplásica , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Células Clonais/patologia , Estudos de Coortes , Progressão da Doença , Neoplasias Pulmonares/patologia , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia
3.
Nature ; 616(7957): 525-533, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37046096

RESUMO

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/etiologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Recidiva Local de Neoplasia/genética , Filogenia , Resultado do Tratamento , Fumar/genética , Fumar/fisiopatologia , Mutagênese , Variações do Número de Cópias de DNA
6.
Nature ; 545(7655): 446-451, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28445469

RESUMO

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem da Célula/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Evolução Molecular , Neoplasias Pulmonares/genética , Metástase Neoplásica/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Biópsia/métodos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Rastreamento de Células , Células Clonais/metabolismo , Células Clonais/patologia , Análise Mutacional de DNA , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Detecção Precoce de Câncer/métodos , Humanos , Limite de Detecção , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Reação em Cadeia da Polimerase Multiplex , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Cuidados Pós-Operatórios/métodos , Reprodutibilidade dos Testes , Carga Tumoral
7.
J Biol Chem ; 297(5): 101223, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34597666

RESUMO

Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the pleura, with few available treatment options. We recently reported that loss of function of the nuclear deubiquitinase BRCA1-associated protein 1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptor 4 (DR4) and death receptor 5 (DR5). Using tissue microarrays of tumor samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptor expression. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wt-BAP1, but not catalytically inactive BAP1 mutant, reduced promoter activities of DR4 and DR5, suggesting deubiquitinase activity is required for the regulation of gene expression. Co-immunoprecipitation studies demonstrated direct binding of BAP1 to the transcription factor Ying Yang 1 (YY1), and chromatin immunoprecipitation assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Knockdown of YY1 also increased DR4 and DR5 expression and sensitivity to TRAIL. These results suggest that BAP1 and YY1 cooperatively repress transcription of TRAIL receptors. Our finding that BAP1 directly regulates the extrinsic apoptotic pathway will provide new insights into the role of BAP1 in the development of MPM and other cancers with frequent BAP1 mutations.


Assuntos
Mesotelioma Maligno/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/biossíntese , Ligante Indutor de Apoptose Relacionado a TNF/biossíntese , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Fator de Transcrição YY1/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Mesotelioma Maligno/genética , Mutação , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Fator de Transcrição YY1/genética
8.
Br J Cancer ; 125(3): 380-389, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34035435

RESUMO

BACKGROUND: The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses. METHODS: In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0-N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT. RESULTS: Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17-0.88) P = 0.0091. CONCLUSION: TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect. TRIAL REGISTRATION: ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/radioterapia , Carcinoma Ductal de Mama/cirurgia , Mastectomia Segmentar/métodos , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Terapia Combinada , Feminino , Humanos , Cuidados Intraoperatórios , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral , Irradiação Corporal Total
9.
N Engl J Med ; 376(22): 2109-2121, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28445112

RESUMO

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Instabilidade Cromossômica , Heterogeneidade Genética , Neoplasias Pulmonares/genética , Mutação , Recidiva Local de Neoplasia/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Evolução Molecular , Exoma , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Filogenia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Análise de Sequência de DNA/métodos
10.
Eur Respir J ; 54(4)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31537697

RESUMO

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/patologia , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/patologia , Escarro/citologia , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Broncoscopia , Carcinoma de Células Grandes/complicações , Carcinoma de Células Grandes/diagnóstico por imagem , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Técnicas Citológicas , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Imagem Óptica , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Medição de Risco , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X , Reino Unido
11.
PLoS Biol ; 12(7): e1001906, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25003521

RESUMO

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Progressão da Doença , Neoplasias Pulmonares/genética , Antígenos de Neoplasias , Biomarcadores Tumorais/análise , Resistencia a Medicamentos Antineoplásicos , Humanos , Estudos Longitudinais , Metástase Neoplásica , Resultado do Tratamento
12.
Lancet ; 383(9917): 603-13, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24224997

RESUMO

BACKGROUND: The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS: TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS: Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION: TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. FUNDING: University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/cirurgia , Feminino , Humanos , Cuidados Intraoperatórios/métodos , Cuidados Intraoperatórios/mortalidade , Estimativa de Kaplan-Meier , Mastectomia Segmentar/métodos , Mastectomia Segmentar/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/prevenção & controle , Radioterapia/métodos , Radioterapia/mortalidade , Resultado do Tratamento
13.
Thorax ; 69(6): 548-57, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24550057

RESUMO

BACKGROUND: Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. METHODS: Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. RESULTS: We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. CONCLUSIONS: Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.


Assuntos
Carcinoma in Situ , Carcinoma de Células Escamosas , Movimento Celular , Neoplasias Pulmonares , Mutação , Lesões Pré-Cancerosas , Neoplasias da Traqueia , Adulto , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Genes p53 , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Neoplasias da Traqueia/genética , Neoplasias da Traqueia/patologia
14.
J Pathol ; 229(4): 608-20, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23208928

RESUMO

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.


Assuntos
Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Lesões Pré-Cancerosas/genética , Animais , Caderinas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Inibição de Contato , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Complexos Multiproteicos , Proteínas do Tecido Nervoso/metabolismo , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Deleção de Sequência , Transdução de Sinais
15.
Am J Respir Crit Care Med ; 185(12): 1316-22, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22505743

RESUMO

RATIONALE: The current management of advanced non-small cell lung cancer (NSCLC) requires differentiation between squamous and nonsquamous subtypes as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whether cytology specimens obtained with EBUS-TBNA are suitable for the subclassification and genotyping of NSCLC. OBJECTIVES: To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC. METHODS: Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across five centers in the United Kingdom between 2009 and 2011. MEASUREMENTS AND MAIN RESULTS: The proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% confidence interval [CI], 73-80). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted odds ratio, 0.50; 95% CI, 0.28-0.82; P = 0.016). EGFR mutation analysis was possible in 107 (90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in patients with NSCLC were 88% (95% CI, 86-91), 72% (95% CI, 66-77), and 91% (95% CI, 89-93), respectively. CONCLUSIONS: This large, multicenter, pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for subtyping of NSCLC and EGFR mutation analysis and that the use of immunohistochemistry reduces the rate of NSCLC-NOS.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Endossonografia/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biópsia por Agulha Fina , Broncoscopia/métodos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Intervalos de Confiança , Citodiagnóstico/métodos , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Excisão de Linfonodo/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Razão de Chances , Prognóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Análise de Sobrevida , Reino Unido
16.
Am J Respir Crit Care Med ; 186(3): 255-60, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22652031

RESUMO

RATIONALE: Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the "gold standard" investigation when a pathological diagnosis is required. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer. OBJECTIVE: To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML. METHODS: Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy. MEASUREMENTS AND MAIN RESULTS: EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77-94%; P < 0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83-95%) and 40% (95% CI, 12-74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P < 0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient. CONCLUSIONS: EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML. Clinical trial registered with ClinicalTrials.gov (NCT00932854).


Assuntos
Doenças Linfáticas/diagnóstico por imagem , Doenças Linfáticas/patologia , Doenças do Mediastino/diagnóstico por imagem , Doenças do Mediastino/patologia , Mediastinoscopia , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Biópsia por Agulha , Broncoscopia/economia , Broncoscopia/métodos , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sensibilidade e Especificidade , Método Simples-Cego , Ultrassonografia de Intervenção/economia
18.
Lancet ; 376(9735): 91-102, 2010 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-20570343

RESUMO

BACKGROUND: After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy. METHODS: Having safely piloted the new technique of single-dose targeted intraoperative radiotherapy with Intrabeam, we launched the TARGIT-A trial on March 24, 2000. In this prospective, randomised, non-inferiority trial, women aged 45 years or older with invasive ductal breast carcinoma undergoing breast-conserving surgery were enrolled from 28 centres in nine countries. Patients were randomly assigned in a 1:1 ratio to receive targeted intraoperative radiotherapy or whole breast external beam radiotherapy, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy. Neither patients nor investigators or their teams were masked to treatment assignment. Postoperative discovery of predefined factors (eg, lobular carcinoma) could trigger addition of external beam radiotherapy to targeted intraoperative radiotherapy (in an expected 15% of patients). The primary outcome was local recurrence in the conserved breast. The predefined non-inferiority margin was an absolute difference of 2.5% in the primary endpoint. All randomised patients were included in the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS: 1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy. Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy. 1025 (92%) patients in the external beam radiotherapy group received the allocated treatment. At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53-2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39-2.31) in the external beam radiotherapy group (difference between groups 0.25%, -1.04 to 1.54; p=0.41). The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3.3%] of 1113 vs external beam radiotherapy, 44 [3.9%] of 1119; p=0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p=0.002). INTERPRETATION: For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks. FUNDING: University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF).


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/radioterapia , Carcinoma Ductal de Mama/cirurgia , Cuidados Intraoperatórios , Mastectomia Segmentar , Idoso , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Dosagem Radioterapêutica , Radioterapia Adjuvante
19.
Am J Pathol ; 177(4): 2034-45, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20724597

RESUMO

Treatment options for triple-receptor negative (ER-/PR-/Her2-) and Her2-overexpressing (ER-/PR-/Her2+) breast cancers with acquired or de novo resistance are limited, and metastatic disease remains incurable. Targeting of growth signaling networks is often constrained by pathway redundancy or growth-independent cancer cell cycles. The cell-cycle protein Cdc7 regulates S phase by promoting DNA replication. This essential kinase acts as a convergence point for upstream growth signaling pathways and is therefore an attractive therapeutic target. We show that increased Cdc7 expression during mammary tumorigenesis is linked to Her2-overexpressing and triple-negative subtypes, accelerated cell cycle progression (P < 0.001), arrested tumor differentiation (P < 0.001), genomic instability (P = 0.019), increasing NPI score (P < 0.001), and reduced disease-free survival (HR = 1.98 [95% CI: 1.27-3.10]; P = 0.003), thus implicating its deregulation in the development of aggressive disease. Targeting Cdc7 with RNAi, we demonstrate that p53-mutant Her2-overexpressing and triple-negative breast cancer cell lines undergo an abortive S phase and apoptotic cell death due to loss of a p53-dependent Cdc7-inhibition checkpoint. In contrast, untransformed breast epithelial cells arrest in G1, remain viable, and are able to resume cell proliferation on recovery of Cdc7 kinase activity. Thus, Cdc7 appears to represent a potent and highly specific anticancer target in Her2-overexpressing and triple-negative breast cancers. Emerging Cdc7 kinase inhibitors may therefore significantly broaden the therapeutic armamentarium for treatment of the aggressive p53-mutant breast cancer subtypes identified in this study.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/metabolismo , Replicação do DNA , Genes p53/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Fase S/fisiologia , Apoptose , Western Blotting , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proliferação de Células , Feminino , Humanos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais
20.
Respirology ; 16(3): 467-72, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21261784

RESUMO

BACKGROUND AND OBJECTIVE: Standard bronchoscopic techniques (transbronchial lung biopsy and endobronchial biopsy) provide a diagnosis in 70% of patients with pulmonary sarcoidosis. Previous data suggest that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high sensitivity in patients with sarcoidosis. The feasibility and utility of combining EBUS-TBNA with standard bronchoscopic techniques is unknown. The aim of this study was to evaluate the feasibility, safety and efficacy of combined EBUS-TBNA and standard bronchoscopic techniques in patients with suspected sarcoidosis and enlarged mediastinal or hilar lymphadenopathy. METHODS: Forty consecutive patients with suspected pulmonary sarcoidosis and enlarged mediastinal or hilar lymph nodes (radiographical stage I and stage II) underwent EBUS-TBNA followed by transbronchial biopsies and endobronchial biopsies under conscious sedation. RESULTS: Thirty-nine out of 40 patients successfully underwent combined EBUS-TBNA and standard bronchoscopy. Twenty-seven patients were diagnosed with sarcoidosis, eight had tuberculosis, two had reactive lymphadenopathy, two had lymphoma and one had metastatic adenocarcinoma. In patients with sarcoidosis, the sensitivity of EBUS-TBNA for detection of non-caseating granulomas was 85%, compared with a sensitivity of 35% for standard bronchoscopic techniques (P < 0.001). The diagnostic yield of combined EBUS-TBNA and bronchoscopy was 93% (P < 0.0001). CONCLUSIONS: Combination of EBUS-TBNA with standard bronchoscopic techniques is safe and feasible, and optimizes the diagnostic yield in patients with pulmonary sarcoidosis and enlarged intrathoracic lymphadenopathy.


Assuntos
Biópsia por Agulha/métodos , Broncoscopia/métodos , Sarcoidose Pulmonar/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adulto , Idoso , Brônquios/diagnóstico por imagem , Brônquios/patologia , Feminino , Humanos , Doenças Linfáticas/diagnóstico , Doenças Linfáticas/diagnóstico por imagem , Doenças Linfáticas/patologia , Linfoma/diagnóstico , Linfoma/diagnóstico por imagem , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Sarcoidose Pulmonar/diagnóstico por imagem , Sarcoidose Pulmonar/patologia , Sensibilidade e Especificidade , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/patologia , Ultrassonografia , Adulto Jovem
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