lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed and are posted here as part of a 12-month trial. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Identification and Verification of a Biomarker Panel for Early Diagnosis of Lung Cancer Patients

37 Pages Posted: 4 Dec 2018

See all articles by Bethany Geary

Bethany Geary

University of Manchester - Stoller Biomarker Discovery Centre; University of Manchester

Michael J. Walker

University of Manchester

Joseph T. Snow

University of Manchester; University of Oxford - Department of Earth Sciences

David C. H. Lee

University of Manchester - Stoller Biomarker Discovery Centre

Maria Pernemalm

Karolinska Institutet - Science for Life Laboratory

Saeedeh Maleki-Dizaji

University of Manchester

Narges Azadbakht

University of Manchester

Sophia Apostolidou

University College London

Julie Barnes

Abcodia

Piotr Krysiak

University of Manchester - Manchester University NHS Foundation Trust

Rajesh Shah

University of Manchester - Manchester University NHS Foundation Trust

Richard Booton

University of Manchester - Manchester University NHS Foundation Trust

Caroline Dive

University of Manchester; Cancer Research UK Lung Cancer Centre of Excellence

Philip A. Crosbie

University of Manchester - Stoller Biomarker Discovery Centre; University College London; University of Manchester - Manchester University NHS Foundation Trust

Anthony Whetton

University of Manchester - Stoller Biomarker Discovery Centre; University of Oxford - Department of Earth Sciences; Cancer Research UK Lung Cancer Centre of Excellence

More...

Abstract

Background:  Lung cancer is the most common cause of cancer related mortality worldwide, characterised by late clinical presentation (49-53% of patients are diagnosed at stage IV) and consequently poor outcomes. One challenge in identifying biomarkers of early disease is the collection of samples from patients prior to symptomatic presentation. An additional complication in determining differential biomarkers arises from protein expression change from non-specific systemic responses and co-morbidities such as Chronic Obstructive Pulmonary Disease (COPD).  

Methods:  We employed isobaric tagging, relative quantification mass spectrometry to analyse protein markers that differed in blood entering and egressing from the tumour bearing lobe of the diseased lung immediately prior to lung resection surgery. These potential biomarkers were assessed as lung cancer early detection biomarkers using the orthogonal mass spectrometry (MS) technique Sequential window acquisition of all theoretical fragment ion spectra (SWATH) MS which we showed had equivalent quantification value to a selected reaction monitoring (SRM) approach.  

Findings:  In a second cohort, SWATH-MS was used to measure 974 proteins in serum samples taken <50 months prior to and at lung cancer diagnosis. Two proteins found to increase in expression egressing from a tumour had value as biomarkers. SWATH-MS profiling followed by machine learning generated a predictive 13 protein panel resulted in a mean AUC of 0.80, an accuracy of 0.78, a sensitivity of 0.79 and a specificity of 0.78.      

Interpretation: Thus, whilst tumour egressing proteins did not contribute significantly to a MS early detection biomarker signature, SWATH-MS and machine learning have great potential value for early detection biomarker algorithms.   

Funding Statement: Mass spectrometry was supported with equipment grants from Bloodwise and Medical Research Council. This work was supported by the CRUK Manchester Centre award (C5759/A25254). CD and ADW are supported by the NIHR Manchester Biomedical Research Centre. CD is also supported via core funding to the CRUK Manchester Institute and via the CRUK Lung Cancer Centre of Excellence (C5759/A20465). The pulmonary vein study was funded by Roy Castle Lung Cancer Foundation (PC) and the North West Lung Centre Charity (PC). UKCTOCS was funded by the Medical Research Council (G9901012 and G0801228), Cancer Research UK (C1479/A2884), the Department of Health and with additional support from The Eve Appeal. Senior investigators at UCL supported by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre.

Declaration of Interests: The authors have no financial conflicts of interest.

Ethics Approval Statement: UKCTOCS was approved by the UK North West Multicentre Research Ethics Committee (North West MREC 00/8/34) with site specific approval from the local regional ethics committees and the Caldicott guardians (data controllers) of the primary care trusts. All women gave written consent for use of samples and data in ethically approved secondary studies. The subset of samples used for the present study has been approved by the Yorkshire & The Humber - Sheffield Research Ethics Committee (REC Ref 15/YH/0044).

Keywords: Biomarker; Lung Cancer; SRM; SWATH; Proteomics; Early Detection

Suggested Citation

Geary, Bethany and Walker, Michael J. and Snow, Joseph T. and Lee, David C. H. and Pernemalm, Maria and Maleki-Dizaji, Saeedeh and Azadbakht, Narges and Apostolidou, Sophia and Barnes, Julie and Krysiak, Piotr and Shah, Rajesh and Booton, Richard and Dive, Caroline and Crosbie, Philip A. and Whetton, Anthony, Identification and Verification of a Biomarker Panel for Early Diagnosis of Lung Cancer Patients (November 24, 2018). Available at SSRN: https://ssrn.com/abstract=3294079

Bethany Geary

University of Manchester - Stoller Biomarker Discovery Centre

Manchester
United Kingdom

University of Manchester

Oxford Road
Manchester, M13 9PL
United Kingdom

Michael J. Walker

University of Manchester

Oxford Road
Manchester, M13 9PL
United Kingdom

Joseph T. Snow

University of Manchester

Oxford Road
Manchester, M13 9PL
United Kingdom

University of Oxford - Department of Earth Sciences

Oxford
United Kingdom

David C. H. Lee

University of Manchester - Stoller Biomarker Discovery Centre

Manchester
United Kingdom

Maria Pernemalm

Karolinska Institutet - Science for Life Laboratory

171 16 Stockholm
Sweden

Saeedeh Maleki-Dizaji

University of Manchester

Oxford Road
Manchester, M13 9PL
United Kingdom

Narges Azadbakht

University of Manchester

Oxford Road
Manchester, M13 9PL
United Kingdom

Sophia Apostolidou

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Julie Barnes

Abcodia

Cambourne, Cambridgeshire
United Kingdom

Piotr Krysiak

University of Manchester - Manchester University NHS Foundation Trust

Oxford Road
Manchester, M13 9PL
United Kingdom

Rajesh Shah

University of Manchester - Manchester University NHS Foundation Trust

Oxford Road
Manchester, M13 9PL
United Kingdom

Richard Booton

University of Manchester - Manchester University NHS Foundation Trust

Oxford Road
Manchester, M13 9PL
United Kingdom

Caroline Dive

University of Manchester

Oxford Road
Manchester, M13 9PL
United Kingdom

Cancer Research UK Lung Cancer Centre of Excellence

United Kingdom

Philip A. Crosbie

University of Manchester - Stoller Biomarker Discovery Centre

Manchester
United Kingdom

University College London

Gower Street
London, WC1E 6BT
United Kingdom

University of Manchester - Manchester University NHS Foundation Trust

Oxford Road
Manchester, M13 9PL
United Kingdom

Anthony Whetton (Contact Author)

University of Manchester - Stoller Biomarker Discovery Centre ( email )

Manchester
United Kingdom

University of Oxford - Department of Earth Sciences ( email )

Oxford
United Kingdom

Cancer Research UK Lung Cancer Centre of Excellence ( email )

United Kingdom

Click here to go to TheLancet.com

Go to TheLancet.com

Paper statistics

Abstract Views
120
Downloads
19