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Exploring the molecular mechanisms underlying pre-diagnostic thrombocytosis in lung cancer patients and evaluating its diagnostic value (PhD)

Start Date Oct 2019

Code E17-Aff, PhD

Status Ongoing

Project Lead
Melissa Barlow
Senior Lead
Prof Willie Hamilton
Institution
University of Exeter
Others
Supervisors: Dr Sarah Bailey, Dr Giordano Pula (both Exeter)

Introduction

Lung cancer is the leading cause of cancer related deaths in the UK. This is partially attributed to patient presentation at advanced stages which is coupled with a poor prognosis. Diagnosing lung cancer at earlier stages may allow patients to be suitable for curative surgery. This project aims to investigate the diagnostic value of pre-diagnostic thrombocytosis in lung cancer patients to ultimately improve lung cancer outcomes.

Thrombocytosis (i.e. a platelet count of over 400 x 109/l in peripheral blood) has been described in cancer patients by several studies and is beginning to be recognised to have diagnostic potential. A recent epidemiological study by Dr Sarah Bailey (listed supervisor) was the first to discover that thrombocytosis has particularly high value as a predictive marker for lung cancer. However, there are several different types of lung cancer (adenocarcinoma, squamous cell carcinoma, large cell carcinoma and small cell lung cancer) and this study did not differentiate between these types. Therefore, this study aims to discover which of the lung cancer subtypes have a stronger association with thrombocytosis, and to also understand the biological mechanisms underlying this association (which remain poorly understood).

Funding

GW4 BioMed MRC Doctoral Training Partnership

Aims & objectives

The main research aims of this study are:

Methodology

To evaluate the relationship between thrombocytosis and the different histological subtypes of lung cancer

A matched cohort design will be used to address this aim. Patients will be selected from CPRD data (and subsequent Cancer Registry linkage) based on a diagnosis of one of the four subtypes of lung cancer (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, small cell lung cancer) recorded in England in the CPRD from 2013 – 2017. The proportion of patients with thrombocytosis for each histological subtype of lung cancer will be compared to a ‘baseline’ group; the cohort of patients with no cancer diagnoses. This comparison will be made using the z-test for independent proportions. Each of the four lung subtype groups will be compared to the comparison group in turn. This will determine the significance, magnitude, and confidence intervals of any difference between the groups and will show which subtypes have a stronger association with a platelet count.

To investigate the underlying mechanisms behind thrombocytosis and the different histological subtypes of lung cancer

Cell lines of the above lung cancer histological subtypes will be tested in vitro for their ability to promote megakaryocyte proliferation, differentiation and platelet formation in a co-culture system. The in vitro data and epidemiological data will then be compared to confirm which lung cancer types are more strongly associated with megakaryocyte modulation and thrombocytosis. Additionally, the biochemical nature of the signal released by lung cancer cells affecting megakaryocyte physiology will be investigated by chromatographic fractionation, proteomics and classical biochemistry techniques which will further enable exploration of the mechanism(s) underlying the cancer-platelet association.

Outputs & impact

We will report our findings in appropriate, high-impact peer reviewed journals. Our research will also be presented at subject-specific conferences, including Cancer Research UK Early Diagnosis conference, The Cancer and Primary Care Research International Network (Ca-PRI) conference, the Society for Academic Primary Care, and the International Society on Thrombosis and Haemostasis.

This study follows on from previous research that influenced NICE guidance on suspected cancer. The present study may help refine guidance for clinicians who suspect lung cancer in patients with thrombocytosis and aid their diagnosis.

Publications

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