Genetic predictors of benefit from adjuvant interferon for melanoma: understanding variation in tumour/host interaction

Lead Research Organisation: University of Leeds
Department Name: Lds Inst Genetics Health & Therapeutics

Abstract

It is likely that an individual‘s response to cancer and to treatment is linked to inherited genetic variation and genetic changes that occur in their tumour. Interferon therapy extends time without recurrence of disease after surgery for melanoma patients but has many side effects and currently we cannot predict who will respond or who will develop side effects. Genetic alterations could be used to help predict a patients‘ response to interferon and we aim to identify these alterations.

In Leeds, we are going to analyse tissue samples removed from patients treated as part of clinical trials with interferon. We will extract genetic material from these samples and identify genetic alterations in both inherited and tumour genes. Using the data that has already been collected for the interferon trials, we will identify genetic alterations that predict benefit from interferon, side effects from interferon and survival in melanoma.

Identification of these genetic factors will help identify those who will obtain an overall benefit from interferon helping clinicians and patients make informed choices about treatment options, and will tell us more about how people‘s inherited characteristics interact with cancer cells.

Technical Summary

Background:
Survival for stage III/IV melanoma patients is poor, and chemotherapy is ineffective. Melanoma is however an immunogenic tumour and there is both evidence that the tumour suppresses the immune system, and that immune-mediated responsiveness to the tumour confers survival benefit. Defects in interferon (IFN) signalling are an important part of tumour induced immune suppression, and there is evidence that adjuvant IFN improves relapse-free survival. In this project, I propose to use mutation detection and gene expression data from primary melanomas and regional lymph nodes (tumour and normal nodal tissue) removed from melanoma patients to understand the genetic events which suppress immune responsiveness, and those which determine benefit from adjuvant IFN therapy. IFN therapy is of limited value in practice because of toxicity and I will investigate the hereditary variation predictive of that toxicity.
Aims:
My objectives are to study:-
1. Germline mutations and tumour gene expression which predict survival overall in melanoma patients and benefit from IFN therapy.
2. Germline genetic variation, which predicts IFN toxicity.
3. Moderation of the effects of germline variation by somatic events in the tumour e.g. loss of receptors.
4. Gene expression patterns in regional normal lymph nodes in melanoma patients, which predict outcome overall and which may be indicative of the suppression of host immunity, and which predict benefit from IFN therapy.
Methodology
- I will access DNA and RNA extracted from formalin-fixed paraffin embedded (FFPE) samples identified by the Leeds group as part of a large study addressed to understanding the determinants of benefit from interferon therapy, in mature sample/data sets from adjuvant clinical trials.
- I will use RT-PCR to study gene expression, exploring platforms such as Illumina DASL, and other platforms designed for FFPE tissue.
- I will use Beckman SNPstream to study candidate genes as biomarkers.
- I will corroborate my findings using immuno-histochemistry and by validation in collaborators data/sample sets.
Scientific opportunities
Biomarker discovery is a current imperative but a difficult aim to accomplish. I will be able to pursue my PhD project within the context of a large scale study which is sufficiently powered to identify useful markers. I hope to significantly increase our understanding of the immunological interaction of the host with tumours.
Medical opportunities
For patients, the successful identification of biomarkers of benefit from IFN would make the only adjuvant therapy shown to have an effect on relapse free survival, accessible.

Publications

10 25 50

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Davies JR (2014) Inherited variation in the PARP1 gene and survival from melanoma. in International journal of cancer

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Jewell R (2010) Patterns of expression of DNA repair genes and relapse from melanoma. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Jewell R (2012) Clinicopathologic features of V600E and V600K melanoma--letter. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Nsengimana J (2018) ß-Catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas. in The Journal of clinical investigation

 
Description Histological and genomic heterogeneity in melanoma
Amount £29,639 (GBP)
Funding ID R&D/PP/1201 
Organisation Leeds Teaching Hospitals Charitable Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2013
 
Description Pilot project award - Research and Development Special Advisory Group Project Support 2009
Amount £34,589 (GBP)
Organisation University of Leeds 
Sector Academic/University
Country United Kingdom
Start 07/2010 
End 10/2011
 
Description Project grant - Gene expression patterns predictive of relapse from melanoma and in relation to subtype
Amount £369,444 (GBP)
Funding ID C8216/A11963 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2010 
End 11/2013
 
Title Collection of biological samples and clinical data 
Description Melanoma tumour samples from patients previously recruited to interferon trials and patients treated with chemotherapy are being stored. Data outlining patient responses to chemotherapy and interferon is also being stored on secure databases. 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact Manuscripts have been published based on results from samples collected from patients treated with chemotherapy as listed in the publication section. 
 
Description Predicting Benefit from Interferon Treatment for Melanoma 
Organisation European Commission
Department EC FP6 Collaborative Projects
Country European Union (EU) 
Sector Academic/University 
PI Contribution We have taken the lead on development of the study protocol and have obtained ethical approval in the UK and regulatory approval in a number of UK centres. The protocol has been made available to European groups. We are receiving and analysing tissue blocks from the UK at our centre.
Collaborator Contribution The University of Sheffield has provided details of patients recruited to the Aim High trial assessing benefit of interferon therapy for patients with melanoma. The trial office has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. The EORTC has provided details of patients recruited to the EORTC melanoma trials assessing benefits of interferon therapy for patients with melanoma. The data centre has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. Chemores are also collecting tumour samples in Europe to identify genetic predictors of interferon response. This sample set includes patients recruited to the Nordic Interferon trials coordinated at the Karolinska Institute. We plan to validate findings by Chemores using our interferon study sample set and pool data with this group to increase the power of our studies. Unfortunately this study has ended in 2014 as other studies have taken priority in Leeds. Samples have been returned to collaborators, but derivative samples will be used for future work.
Impact As this study has terminated, samples have been returned. The Leeds group has retained derivative samples for future study however.
Start Year 2008
 
Description Predicting Benefit from Interferon Treatment for Melanoma 
Organisation European Organisation for Research and Treatment of Cancer (EORTC)
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution We have taken the lead on development of the study protocol and have obtained ethical approval in the UK and regulatory approval in a number of UK centres. The protocol has been made available to European groups. We are receiving and analysing tissue blocks from the UK at our centre.
Collaborator Contribution The University of Sheffield has provided details of patients recruited to the Aim High trial assessing benefit of interferon therapy for patients with melanoma. The trial office has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. The EORTC has provided details of patients recruited to the EORTC melanoma trials assessing benefits of interferon therapy for patients with melanoma. The data centre has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. Chemores are also collecting tumour samples in Europe to identify genetic predictors of interferon response. This sample set includes patients recruited to the Nordic Interferon trials coordinated at the Karolinska Institute. We plan to validate findings by Chemores using our interferon study sample set and pool data with this group to increase the power of our studies. Unfortunately this study has ended in 2014 as other studies have taken priority in Leeds. Samples have been returned to collaborators, but derivative samples will be used for future work.
Impact As this study has terminated, samples have been returned. The Leeds group has retained derivative samples for future study however.
Start Year 2008
 
Description Predicting Benefit from Interferon Treatment for Melanoma 
Organisation Karolinska Institute
Department Nordic Melanoma Cooperative Group
Country Sweden 
Sector Academic/University 
PI Contribution We have taken the lead on development of the study protocol and have obtained ethical approval in the UK and regulatory approval in a number of UK centres. The protocol has been made available to European groups. We are receiving and analysing tissue blocks from the UK at our centre.
Collaborator Contribution The University of Sheffield has provided details of patients recruited to the Aim High trial assessing benefit of interferon therapy for patients with melanoma. The trial office has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. The EORTC has provided details of patients recruited to the EORTC melanoma trials assessing benefits of interferon therapy for patients with melanoma. The data centre has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. Chemores are also collecting tumour samples in Europe to identify genetic predictors of interferon response. This sample set includes patients recruited to the Nordic Interferon trials coordinated at the Karolinska Institute. We plan to validate findings by Chemores using our interferon study sample set and pool data with this group to increase the power of our studies. Unfortunately this study has ended in 2014 as other studies have taken priority in Leeds. Samples have been returned to collaborators, but derivative samples will be used for future work.
Impact As this study has terminated, samples have been returned. The Leeds group has retained derivative samples for future study however.
Start Year 2008
 
Description Predicting Benefit from Interferon Treatment for Melanoma 
Organisation University of Sheffield
Department Academic Unit of Clinical Oncology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have taken the lead on development of the study protocol and have obtained ethical approval in the UK and regulatory approval in a number of UK centres. The protocol has been made available to European groups. We are receiving and analysing tissue blocks from the UK at our centre.
Collaborator Contribution The University of Sheffield has provided details of patients recruited to the Aim High trial assessing benefit of interferon therapy for patients with melanoma. The trial office has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. The EORTC has provided details of patients recruited to the EORTC melanoma trials assessing benefits of interferon therapy for patients with melanoma. The data centre has sent these details to principal investigators in recruiting centres, to enable these centres to trace tissue blocks for our research. Chemores are also collecting tumour samples in Europe to identify genetic predictors of interferon response. This sample set includes patients recruited to the Nordic Interferon trials coordinated at the Karolinska Institute. We plan to validate findings by Chemores using our interferon study sample set and pool data with this group to increase the power of our studies. Unfortunately this study has ended in 2014 as other studies have taken priority in Leeds. Samples have been returned to collaborators, but derivative samples will be used for future work.
Impact As this study has terminated, samples have been returned. The Leeds group has retained derivative samples for future study however.
Start Year 2008
 
Description Predicting Response to Chemotherapy in Melanoma: The role of DNA repair genes 
Organisation European Commission
Department EC FP6 Collaborative Projects
Country European Union (EU) 
Sector Academic/University 
PI Contribution We have developed the study protocol and obtained ethical approval for this work in the UK. We have collected chemotherapy response data and samples for patients treated at Leeds Teaching Hospitals. We have coordinated the collaboration, with samples from Europe and the UK being analysed in Leeds. Preliminary data from this work has been used in collaborative studies with the University of Nottingham and Karolinska Institute.
Collaborator Contribution For this study, we are collecting tumour blocks from patients treated with chemotherapy. Members of the collaboration in the UK and Europe have provided samples from chemotherapy treated patients. The EORTC are providing chemotherapy response data for patients recruited to the EORTC 18032 trial. For patients not treated as part of trials, data has been collected by treating clinicans. This data has been linked to results from tumour blocks to identify genes associated with response to chemotherapy. The University of Nottingham have undertaken functional cellular work to complement the results of this study for publication. The Department of Oncology-Pathology at the Karolinska Institute have been performing additional analyses on the tumour samples to add to the results of this study.
Impact Preliminary data is being used in collaborative publications with the University of Nottingham and Karolinska Institute. This has led to recent publications listed in the publication section. Sample collection continues to increase the power of the primary study.
Start Year 2010
 
Description Predicting Response to Chemotherapy in Melanoma: The role of DNA repair genes 
Organisation European Organisation for Research and Treatment of Cancer (EORTC)
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution We have developed the study protocol and obtained ethical approval for this work in the UK. We have collected chemotherapy response data and samples for patients treated at Leeds Teaching Hospitals. We have coordinated the collaboration, with samples from Europe and the UK being analysed in Leeds. Preliminary data from this work has been used in collaborative studies with the University of Nottingham and Karolinska Institute.
Collaborator Contribution For this study, we are collecting tumour blocks from patients treated with chemotherapy. Members of the collaboration in the UK and Europe have provided samples from chemotherapy treated patients. The EORTC are providing chemotherapy response data for patients recruited to the EORTC 18032 trial. For patients not treated as part of trials, data has been collected by treating clinicans. This data has been linked to results from tumour blocks to identify genes associated with response to chemotherapy. The University of Nottingham have undertaken functional cellular work to complement the results of this study for publication. The Department of Oncology-Pathology at the Karolinska Institute have been performing additional analyses on the tumour samples to add to the results of this study.
Impact Preliminary data is being used in collaborative publications with the University of Nottingham and Karolinska Institute. This has led to recent publications listed in the publication section. Sample collection continues to increase the power of the primary study.
Start Year 2010
 
Description Predicting Response to Chemotherapy in Melanoma: The role of DNA repair genes 
Organisation Karolinska Institute
Department Department of Oncology-Pathology
Country Sweden 
Sector Academic/University 
PI Contribution We have developed the study protocol and obtained ethical approval for this work in the UK. We have collected chemotherapy response data and samples for patients treated at Leeds Teaching Hospitals. We have coordinated the collaboration, with samples from Europe and the UK being analysed in Leeds. Preliminary data from this work has been used in collaborative studies with the University of Nottingham and Karolinska Institute.
Collaborator Contribution For this study, we are collecting tumour blocks from patients treated with chemotherapy. Members of the collaboration in the UK and Europe have provided samples from chemotherapy treated patients. The EORTC are providing chemotherapy response data for patients recruited to the EORTC 18032 trial. For patients not treated as part of trials, data has been collected by treating clinicans. This data has been linked to results from tumour blocks to identify genes associated with response to chemotherapy. The University of Nottingham have undertaken functional cellular work to complement the results of this study for publication. The Department of Oncology-Pathology at the Karolinska Institute have been performing additional analyses on the tumour samples to add to the results of this study.
Impact Preliminary data is being used in collaborative publications with the University of Nottingham and Karolinska Institute. This has led to recent publications listed in the publication section. Sample collection continues to increase the power of the primary study.
Start Year 2010
 
Description Predicting Response to Chemotherapy in Melanoma: The role of DNA repair genes 
Organisation Leeds Teaching Hospitals NHS Trust
Department Dermatology Department
Country United Kingdom 
Sector Hospitals 
PI Contribution We have developed the study protocol and obtained ethical approval for this work in the UK. We have collected chemotherapy response data and samples for patients treated at Leeds Teaching Hospitals. We have coordinated the collaboration, with samples from Europe and the UK being analysed in Leeds. Preliminary data from this work has been used in collaborative studies with the University of Nottingham and Karolinska Institute.
Collaborator Contribution For this study, we are collecting tumour blocks from patients treated with chemotherapy. Members of the collaboration in the UK and Europe have provided samples from chemotherapy treated patients. The EORTC are providing chemotherapy response data for patients recruited to the EORTC 18032 trial. For patients not treated as part of trials, data has been collected by treating clinicans. This data has been linked to results from tumour blocks to identify genes associated with response to chemotherapy. The University of Nottingham have undertaken functional cellular work to complement the results of this study for publication. The Department of Oncology-Pathology at the Karolinska Institute have been performing additional analyses on the tumour samples to add to the results of this study.
Impact Preliminary data is being used in collaborative publications with the University of Nottingham and Karolinska Institute. This has led to recent publications listed in the publication section. Sample collection continues to increase the power of the primary study.
Start Year 2010
 
Description Predicting Response to Chemotherapy in Melanoma: The role of DNA repair genes 
Organisation Nottingham University Hospitals NHS Trust
Department Oncology Nottingham
Country United Kingdom 
Sector Public 
PI Contribution We have developed the study protocol and obtained ethical approval for this work in the UK. We have collected chemotherapy response data and samples for patients treated at Leeds Teaching Hospitals. We have coordinated the collaboration, with samples from Europe and the UK being analysed in Leeds. Preliminary data from this work has been used in collaborative studies with the University of Nottingham and Karolinska Institute.
Collaborator Contribution For this study, we are collecting tumour blocks from patients treated with chemotherapy. Members of the collaboration in the UK and Europe have provided samples from chemotherapy treated patients. The EORTC are providing chemotherapy response data for patients recruited to the EORTC 18032 trial. For patients not treated as part of trials, data has been collected by treating clinicans. This data has been linked to results from tumour blocks to identify genes associated with response to chemotherapy. The University of Nottingham have undertaken functional cellular work to complement the results of this study for publication. The Department of Oncology-Pathology at the Karolinska Institute have been performing additional analyses on the tumour samples to add to the results of this study.
Impact Preliminary data is being used in collaborative publications with the University of Nottingham and Karolinska Institute. This has led to recent publications listed in the publication section. Sample collection continues to increase the power of the primary study.
Start Year 2010
 
Description Predicting Response to Chemotherapy in Melanoma: The role of DNA repair genes 
Organisation The Christie NHS Foundation Trust
Department Oncology Christie NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have developed the study protocol and obtained ethical approval for this work in the UK. We have collected chemotherapy response data and samples for patients treated at Leeds Teaching Hospitals. We have coordinated the collaboration, with samples from Europe and the UK being analysed in Leeds. Preliminary data from this work has been used in collaborative studies with the University of Nottingham and Karolinska Institute.
Collaborator Contribution For this study, we are collecting tumour blocks from patients treated with chemotherapy. Members of the collaboration in the UK and Europe have provided samples from chemotherapy treated patients. The EORTC are providing chemotherapy response data for patients recruited to the EORTC 18032 trial. For patients not treated as part of trials, data has been collected by treating clinicans. This data has been linked to results from tumour blocks to identify genes associated with response to chemotherapy. The University of Nottingham have undertaken functional cellular work to complement the results of this study for publication. The Department of Oncology-Pathology at the Karolinska Institute have been performing additional analyses on the tumour samples to add to the results of this study.
Impact Preliminary data is being used in collaborative publications with the University of Nottingham and Karolinska Institute. This has led to recent publications listed in the publication section. Sample collection continues to increase the power of the primary study.
Start Year 2010
 
Description Predicting Response to Chemotherapy in Melanoma: The role of DNA repair genes 
Organisation University Duisburg-Essen
Department Department of Dermatology
Country Germany 
Sector Academic/University 
PI Contribution We have developed the study protocol and obtained ethical approval for this work in the UK. We have collected chemotherapy response data and samples for patients treated at Leeds Teaching Hospitals. We have coordinated the collaboration, with samples from Europe and the UK being analysed in Leeds. Preliminary data from this work has been used in collaborative studies with the University of Nottingham and Karolinska Institute.
Collaborator Contribution For this study, we are collecting tumour blocks from patients treated with chemotherapy. Members of the collaboration in the UK and Europe have provided samples from chemotherapy treated patients. The EORTC are providing chemotherapy response data for patients recruited to the EORTC 18032 trial. For patients not treated as part of trials, data has been collected by treating clinicans. This data has been linked to results from tumour blocks to identify genes associated with response to chemotherapy. The University of Nottingham have undertaken functional cellular work to complement the results of this study for publication. The Department of Oncology-Pathology at the Karolinska Institute have been performing additional analyses on the tumour samples to add to the results of this study.
Impact Preliminary data is being used in collaborative publications with the University of Nottingham and Karolinska Institute. This has led to recent publications listed in the publication section. Sample collection continues to increase the power of the primary study.
Start Year 2010
 
Description Primary Melanoma Tumour Ulceration 
Organisation Lund University
Department Faculty of Medicine
Country Sweden 
Sector Academic/University 
PI Contribution Using sample collection in Leeds, we have identified clinico-pathological features and gene expression profiles associated with primary tumour ulceration. These results have been validated using a sample set from Lund University. The University of Nottingham provided immunohistochemical data from primary tumours, which we have analysed to expand this analysis.
Collaborator Contribution The University of Nottingham provided immunohistochemical data from primary tumours for our analyses. Gene expression data has been validated in an independent sample set provided by the Melanoma Genomic Unit at Lund University.
Impact Data has been presented in an oral presentation at the Paris Melanoma Conference, April 2012. The abstract for this work was awarded with an 'Outstanding Abstract' award. Results of the study have been recently published as listed in the publication section.
Start Year 2012
 
Description Primary Melanoma Tumour Ulceration 
Organisation University of Nottingham
Department Academic Oncology Research Group
Country United Kingdom 
Sector Academic/University 
PI Contribution Using sample collection in Leeds, we have identified clinico-pathological features and gene expression profiles associated with primary tumour ulceration. These results have been validated using a sample set from Lund University. The University of Nottingham provided immunohistochemical data from primary tumours, which we have analysed to expand this analysis.
Collaborator Contribution The University of Nottingham provided immunohistochemical data from primary tumours for our analyses. Gene expression data has been validated in an independent sample set provided by the Melanoma Genomic Unit at Lund University.
Impact Data has been presented in an oral presentation at the Paris Melanoma Conference, April 2012. The abstract for this work was awarded with an 'Outstanding Abstract' award. Results of the study have been recently published as listed in the publication section.
Start Year 2012