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.
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.
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.
