Gene amplification within chromosome 3q in preinvasive bronchial lesions - towards targets for novel biomarkers and ther

Lead Research Organisation: University College London
Department Name: Unlisted

Abstract

Lung cancer is the most common cause of death from cancer in both males and females in the United Kingdom. The survival after diagnosis is the worst of all common cancers. The main reasons for this are that patients have advanced disease when diagnosed and that currently available treatments are not very effective. New approaches are required.

We have collected a number of samples from patients‘ lungs with early changes known as preinvasive lesions. These may have the potential to progress to lung cancer. This collection is unique. Our preliminary analysis has shown that an area of chromosome 3 tends to be abnormal in these samples. This agrees with work from other laboratories that suggests this part of chromosome 3 is abnormal in lung cancer. We want to further characterise this abnormality and hopefully gain insights into the particular genes involved. Such genes could provide a biomarker which would predict risk of developing lung cancer. In addition the proteins coded for by these genes may be responsible for the progression of the preinvasive lesion and therefore they may represent targets suitable for new drug treatments.

Technical Summary

Lung cancer is responsible for more deaths than any other cancer in the UK. Novel approaches to early detection and treatment are desperately required. Each tumour harbours numerous genomic aberrations including gene amplification. It is proposed that amplicons harbour oncogenes which confer a growth advantage, thereby contributing to the malignant phenotype. Such amplified oncogenes may serve as molecular biomarkers and may also be excellent targets for novel therapies. Classically genome amplification has been analysed using Comparative Genomic Hybridisation (CGH), a low resolution technique which compares the relative abundance of chromosomal regions in tumour to that of normal DNA. The host group at UCL has a unique archive consisting of serial samples of preinvasive bronchial epithelial lesions from patients enrolled in a surveillance project, giving an unrivalled opportunity to study the dynamics of squamous cell carcinoma evolution. Preliminary data from these samples, using CGH to test the whole genome, demonstrates that amplification of chromosome 3q is the most frequent genomic event in early or preinvasive lesions. The hypothesis for this project has two elements: firstly that a commonly amplified region of chromosome 3q will contain an oncogene(s) involved in the progression of preinvasive squamous lung cancer; and secondly, that amplicons will evolve with progression of preinvasive lesions. To test this I will:
1) Precisely delineate and characterise the 3q amplicon in this unique chronological series of bronchial preinvasive lesions using a novel technique - Molecular Counting by Limiting Dilution (MCLD):
2) Use genomic databases and data from 1) to identify candidate oncogene(s) within the amplicon.
We have established a collaboration with Dr P Dear (MRC-LMB Cambridge) to use MCLD to define the amplicon boundaries from each sample. Results will be compared a) from all samples to define the smallest common region of chromosome 3q amplification; and b) from sequential biopsies of specific lesions to determine if amplicons evolve with lesion progression. By interrogating genomic databases I will identify candidate oncogenes in the amplified region. Once candidate genes are identified I will consider expression and functional analyses as appropriate. It is expected that these studies will provide basic insights into the dynamics of amplicon development. Furthermore, successful identification of an oncogene involved in early lung cancer evolution may provide a novel target suitable for either development as a biomarker or, as a target for therapeutic intervention, and therefore could have implications for improving the appalling mortality associated with this condition.

Publications

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Day E (2013) IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer. in International journal of experimental pathology

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Gao F (2015) Microdroplet digital PCR: detection and quantitation of biomarkers in archived tissue and serial plasma samples in patients with lung cancer. in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

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Ivey A (2016) Assessment of Minimal Residual Disease in Standard-Risk AML. in The New England journal of medicine

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Karampini E (2016) Circulating DNA in solid organ cancers-analysis and clinical application. in QJM : monthly journal of the Association of Physicians

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McCaughan F (2009) Molecular copy-number counting: potential of single-molecule diagnostics. in Expert review of molecular diagnostics

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McCaughan F (2010) Single-molecule genomics. in The Journal of pathology

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McCaughan F (2010) Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer. in American journal of respiratory and critical care medicine

 
Guideline Title Epidemiology of lung cancer: diagnosis and management of lung cancer: American College of Chest Physicians evidence-based clinical practice guidelines
Description ACCP guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
 
Description Lead Lung Cancer
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Reorganised service delivery
 
Description Challenge Fund
Amount £97,000 (GBP)
Organisation King’s Health Partners 
Sector Academic/University
Country United Kingdom
Start 04/2014 
End 04/2015
 
Description MRC Career Development Fellowship
Amount £150,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2010 
End 01/2012
 
Description MRCT
Amount £21,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2011 
End 06/2012
 
Description NC3R Studentship
Amount £90,000 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description Roy Castle
Amount £24,000 (GBP)
Organisation Roy Castle Lung Cancer Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 08/2013
 
Description Roy Castle Lung Cancer Fund
Amount £141,000 (GBP)
Organisation Roy Castle Lung Cancer Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 04/2018
 
Description Wellcome Trust Intermediate Fellowship
Amount £875,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2012 
End 05/2017
 
Title Copy-number Analysis 
Description Single molecule genomics technique 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Publication only to date. Others pending 
 
Description Circulating Biomarkers 
Organisation King's College London
Department NIHR Biomedical Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Development novel protocols for ctDNA detecton and quantitation
Collaborator Contribution Patient samples; infrastructure
Impact Abstracts only to date. More funding attracted
Start Year 2012
 
Description HAPPY Mapping Cancer Genomes 
Organisation University of Cambridge
Department Department of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Technical expertise and experimental work
Collaborator Contribution Application novel methodology
Impact Publication submitted
Start Year 2007
 
Description KHP Thoracic Tissue 
Organisation National Institute for Health Research
Department NIHR Comprehensive Biomedical Research Centre, Guy's and St Thomas
Country United Kingdom 
Sector Public 
PI Contribution This is an an active and dynamic collaboration investigating pathogenic mechanisms in lung cancer and circulating biomarkers.
Collaborator Contribution Access to specimens
Impact Publications and abstracts
Start Year 2013
 
Description Multilocus integrated evaluation of CNAs and sequence mutations 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution Technique development. Application to diagnostic specimens
Collaborator Contribution Supply of materialsSupply of Materials
Impact Multidisciplinary - clinical teams and basic scientists
Start Year 2011
 
Description Multilocus integrated evaluation of CNAs and sequence mutations 
Organisation Papworth Hospital NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Technique development. Application to diagnostic specimens
Collaborator Contribution Supply of materialsSupply of Materials
Impact Multidisciplinary - clinical teams and basic scientists
Start Year 2011
 
Description Papworth 
Organisation Papworth Hospital NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Biological understanding
Collaborator Contribution Papworth colleagues have contributed a tissue microarray
Impact For next year's return - paper under review
Start Year 2015
 
Description Re-SEARCH trial 
Organisation University of Leeds
Department Leeds Institute of Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Writing grant proposal
Collaborator Contribution Advice
Impact Multicentre clinical trial now funded
Start Year 2006
 
Description Squamous Carcinoma 
Organisation University of Leeds
Department Leeds Institute of Biomedical & Clinical Sciences (LIBACS)
Country United Kingdom 
Sector Academic/University 
PI Contribution Sample supply
Collaborator Contribution Sample analysis
Impact Not as yet
Start Year 2012
 
Title Circulating Tumour DNA 
Description Digital PCR for circulating nucleic acid biomarkers 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact First paper in press. Presentations at national meetings.