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1.  Spatial and temporal diversity in genomic instability processes defines lung cancer evolution 
Science (New York, N.Y.)  2014;346(6206):251-256.
Spatial and temporal dissection of the genomic changes occurring during the evolution of human non–small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.
PMCID: PMC4636050  PMID: 25301630
3.  Primary synovial sarcoma of the lung: can haemothorax be the first manifestation? 
Journal of Thoracic Disease  2014;6(12):E249-E251.
Primary pulmonary synovial sarcomas represent a rare clinical entity and account for approximately 0.5% of lung malignancies. We report the case of a 30-year-old male who presented clinically with haemothorax. Imaging revealed a complex collection obscuring a multi-lobulated mass in the right lower lobe of the lung. He underwent a right thoracotomy for evacuation of collection and surgical resection of his pulmonary mass. Histological analysis confirmed a grade 3 monophasic fibrous synovial sarcoma of the lung with infiltration to adjacent pleura, causing his initial haemothorax. Postoperative period was uneventful and patient was referred to the oncology team for further management. Primary pulmonary synovial sarcoma, though rare, should remain an important differential when considering lung malignancies, as complete surgical resection is the mainstay of treatment.
PMCID: PMC4283313  PMID: 25590001
Primary pulmonary synovial sarcoma; haemothorax
4.  Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study 
PLoS Biology  2014;12(7):e1001906.
TRACERx, a prospective study of patients with primary non-small cell lung cancer, aims to map the genomic landscape of lung cancer by tracking clonal heterogeneity and tumour evolution from diagnosis to relapse.
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.
PMCID: PMC4086714  PMID: 25003521
5.  Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors 
eLife  2013;2:e00966.
Lineage tracing approaches have provided new insights into the cellular mechanisms that support tissue homeostasis in mice. However, the relevance of these discoveries to human epithelial homeostasis and its alterations in disease is unknown. By developing a novel quantitative approach for the analysis of somatic mitochondrial mutations that are accumulated over time, we demonstrate that the human upper airway epithelium is maintained by an equipotent basal progenitor cell population, in which the chance loss of cells due to lineage commitment is perfectly compensated by the duplication of neighbours, leading to “neutral drift” of the clone population. Further, we show that this process is accelerated in the airways of smokers, leading to intensified clonal consolidation and providing a background for tumorigenesis. This study provides a benchmark to show how somatic mutations provide quantitative information on homeostatic growth in human tissues, and a platform to explore factors leading to dysregulation and disease.
eLife digest
As air flows into our lungs, the lining of the nasal cavity, the throat and the rest of the respiratory tract prevents microbes, bacteria, dust and other small particles from entering the lungs. The lining of these airways is made up of many different types of cells, which must be continuously replaced as they become damaged. Experiments in mice have shown that cells called basal cells act as progenitor cells to keep the lining supplied with new cells. Progenitor cells are similar to stem cells: they divide to make, on average, one copy of themselves and one mature cell of another type (such as a secretory cell). This ensures that healthy supply of progenitor cells is maintained for the future. However, it is not clear whether this process takes place at the level of individual progenitor cells or as an average for a population of cells.
Teixeira et al. have now performed a study which shows that basal cells achieve this balance as a result of averaging. The study took advantage of the fact that cellular organelles called mitochondria have their own DNA, which gradually accumulates mutations over time. This makes it possible to identify groups of cells that are descended from a single progenitor cell because they will all contain the same mitochondrial mutation.
By studying lung tissue from seven individuals, Teixeira et al. were able to identify clusters of related cells and found that, as expected, the size of the clusters increased with age. And by applying a mathematical model across all the cells in the study, it was discovered that whenever one basal progenitor cell committed to a particular fate, another progenitor cell duplicated itself: however, this balancing process happened in a random manner across a large number of cells, and not at the level of individual progenitor cells. Interestingly, it was found random cell division happened among smokers too, but was accelerated. This leads to clusters of identical cells forming more quickly in smokers than in non-smokers. In addition to providing further insights into the origins of lung cancer, the statistical methods developed by Teixeira et al. could be used to analyse the behaviour of many other types of stem or progenitor cells.
PMCID: PMC3804062  PMID: 24151545
Human lineage tracing; mtDNA mutations; lung basal progenitor stem cells; stochastic homeostasis; airways; Human
6.  Endobronchial Ultrasound–guided Transbronchial Needle Aspiration Prevents Mediastinoscopies in the Diagnosis of Isolated Mediastinal Lymphadenopathy 
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 (NCT00932854).
PMCID: PMC3423452  PMID: 22652031
endobronchial ultrasound; mediastinal lymphadenopathy; sarcoidosis; tuberculosis; lymphoma
7.  Suitability of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Specimens for Subtyping and Genotyping of Non–Small Cell Lung Cancer 
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.
PMCID: PMC3378660  PMID: 22505743
endobronchial ultrasound; non–small cell lung cancer; adenocarcinoma; EGFR mutation; NSCLC-NOS
8.  Suitability of EBUS-TBNA Specimens for Subtyping and Genotyping of NSCLC: A Multi-Centre Study of 774 Patients 
The current management of advanced non-small cell lung cancer (NSCLC) requires differentiation between squamous and non-squamous sub-types 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 sub-classification and genotyping of NSCLC.
To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC.
Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across 5 centres 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% CI 73% - 80%). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted OR 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 was 88% (95% CI 86% - 91%), 72% (95% CI 66% - 77%) and 91% (95% CI 89% - 93%) respectively.
This large multi-centre pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for sub-typing of NSCLC and EGFR mutation analysis and that use of immunohistochemistry reduces the rate of NSCLC-NOS.
PMCID: PMC3378660  PMID: 22505743
Endobronchial ultrasound; non-small cell lung cancer; adenocarcinoma; EGFR mutation; squamous cell carcinoma; NSCLC-NOS
9.  Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Diagnosis of Intrathoracic Lymphadenopathy in Patients with Extrathoracic Malignancy 
Mediastinal lymphadenopathy in patients with an extrathoracic malignancy is a common clinical scenario. Invasive sampling of intrathoracic lymph nodes may be performed by mediastinoscopy or endoscopic ultrasound-guided fine needle aspiration. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an alternative to mediastinoscopy and endoscopic ultrasound in patients with lung cancer and sarcoidosis. The utility of EBUS-TBNA in patients with extrathoracic malignancy was evaluated.
Consecutive patients who were suspected to have intrathoracic lymph node metastases from an extrathoracic malignancy underwent EBUS-TBNA. When EBUS-TBNA did not provide a specific diagnosis, patients underwent mediastinoscopy or clinical follow-up of at least 6 months duration.
One hundred sixty-one patients meeting the inclusion criteria underwent EBUS-TBNA in five UK centers over a 3-year period. EBUS-TBNA diagnosed mediastinal or hilar metastases in 71 (44%) patients, new lung cancer in 20 (12%) patients, and sarcoidosis in 14 (9%) patients. The sensitivity, negative predictive value for malignancy, and overall accuracy for EBUS-TBNA were 87%, 73% and 88%, respectively. One hundred ten (68%) patients in the study had a final diagnosis of malignant intrathoracic lymphadenopathy.
Because of the high prevalence of alternative diagnoses, pathological evaluation is important in patients with extrathoracic malignancy and suspected mediastinal or hilar lymph node metastases. EBUS-TBNA is a safe and sensitive technique and may be considered a first-line investigation in these patients.
PMCID: PMC3361007  PMID: 21792077
Endobronchial ultrasound; Mediastinal lymphadenopathy; Breast cancer; Lung cancer
10.  Combination of endobronchial ultrasound-guided transbronchial needle aspiration with standard bronchoscopic techniques for the diagnosis of stage I and stage II pulmonary sarcoidosis 
Respirology (Carlton, Vic.)  2011;16(3):467-472.
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.
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.
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 noncaseating 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).
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.
PMCID: PMC3361303  PMID: 21261784
endobronchial ultrasound; mediastinal lymphadenopathy; sarcoidosis; transbronchial biopsy
11.  Pulmonary mass in a 19-year-old male 
Thorax  2011;67(5):468-470.
PMCID: PMC3361305  PMID: 22106020
12.  Progressive 3q Amplification Consistently Targets SOX2 in Preinvasive Squamous Lung Cancer 
Rationale: Amplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation.
Objectives: To perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades.
Methods: We use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals.
Measurements and Main Results: We demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression.
Conclusions: These findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.
PMCID: PMC2902760  PMID: 20299530
bronchial dysplasia; squamous lung cancer; gene amplification; molecular copy-number counting; SOX2
13.  Surveillance for the detection of early lung cancer in patients with bronchial dysplasia 
Thorax  2006;62(1):43-50.
The natural history of bronchial preinvasive lesions and the risk of developing lung cancer in patients with these lesions are not clear. Previous studies have treated severe dysplasia and carcinoma in situ (CIS) on the assumption that most will progress to invasive carcinoma.
To define the natural history of preinvasive lesions and assess lung cancer risk in patients with these lesions.
Most preinvasive lesions will not progress to invasive carcinoma but patients with these lesions will be at high risk.
A cohort of patients with preinvasive lesions underwent fluorescence bronchoscopy every 4–12 months and computed tomography of the chest annually. The main end point was the development of invasive carcinoma.
22 patients with 53 lesions were followed up for 12–85 months. 11 cancers were diagnosed in 9 patients. Of the 36 high‐grade lesions (severe dysplasia and CIS), 6 progressed to invasive cancers. 5 separate cancers developed at remote sites in patients with high‐grade lesions. All cancers were N0M0 and curative treatment was given to 8 of the 9 patients. The cumulative risk of developing lung cancer in a patient with a high‐grade lesion was 33% and 54% at 1 and 2 years, respectively. Of the 17 low‐grade lesions, none progressed to invasive carcinoma.
Although the risk of malignant progression of individual preinvasive lesions is relatively small, patients with high‐grade lesions are at high risk of lung cancer. Surveillance facilitated early detection and treatment with curative intent in most patients.
PMCID: PMC2111271  PMID: 16825337
14.  Polarized Localization of Epithelial CXCL11 in Chronic Obstructive Pulmonary Disease and Mechanisms of T Cell Egression1 
The exit of lymphocytes from the interstitium of the lung, across the bronchial epithelium and into the airway lumen, is known as egression, or luminal clearance. Egression is important for immune surveillance and the resolution of inflammation, but the mechanisms involved are unknown. We show that egression of human T cells across the bronchial epithelium is a multistep process, driven in part by a polarized transepithelial gradient of CXCL11 that is up-regulated in patients with chronic obstructive airways disease. Previous studies have shown that T cells can migrate across a disrupted bronchial epithelium, but we provide evidence that egression does not require epithelial injury, and can take place across an intact epithelial barrier. After negotiating the extracellular matrix, the T cell adheres to the basal surface of the bronchial epithelial cell using α4 and leukocyte function associated-1 integrins before crossing the epithelium in an leukocyte function associated-1-dependent way. We demonstrate an egression-dependent decrease in transepithelial resistance across the epithelium without gross alteration in tight-junction proteins. The process of egression has been relatively overlooked when considering the control of leukocyte trafficking in the lung and other epithelial organs. This study highlights the role of the respiratory epithelium in the trafficking of T lymphocytes from the pulmonary interstitium and into the large airways, during the onset and resolution of pulmonary inflammation.
PMCID: PMC2274894  PMID: 18209084
15.  LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development 
The Journal of Pathology  2013;229(4):608-620.
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.
PMCID: PMC3806036  PMID: 23208928
EGFR; LRIG1; squamous cell carcinoma; lung cancer; pre-invasive; E-cadherin; cell-cell contact
16.  Cell migration leads to spatially distinct but clonally related airway cancer precursors 
Thorax  2014;69(6):548-557.
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.
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.
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.
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.
PMCID: PMC4033139  PMID: 24550057
Lung Cancer; Airway Epithelium

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