Wind, T.T. (2015) Functional genomic analysis of melanoma to identify markers for clinical response to adjuvant immunotherapy in a population based registry. thesis, Medicine.
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Abstract
Introduction - Melanoma is the most aggressive form of skin cancer, accounting for nearly 90% of all deaths due to cutaneous malignancies and bearing a five-year survival rate of 16%. For long, this has been attributed to the absence of life-elongating therapeutic options in end-stage disease. Newly developed drugs, ipilimumab, nivolumab and pembrolizumab have established a success in terms of survival in a subgroup of melanoma patients. However, because the adverse effects of these drugs can be hazardous and in some cases even lethal, patient selection should be undertaken with caution, especially in the adjuvant therapy setting. Markers that can predict survival rates for melanoma patients would be useful to select patients that apply for adjuvant therapy. In this study we try to identify immune-related genes expressed by melanoma cells that correlate with clinical outcome and response to immunotherapy. Here, we present the results of two primary goals in order to provide a platform for this research, namely: 1) to create an overview of a cohort of patients diagnosed with melanoma and to evaluate survival of patients in this cohort, and 2) the identification of highly expressed immune-related genes in melanoma cells by using Functional Genomic mRNA Analysis (FGA). Methods – The cohort was created using data from the information from Pathologie Freisland. Patient characteristics were obtained from patients files in the MCL, as were data on treatment, follow-up and survival. Survival analysis was performed using the Kaplan-Meier estimation. Variables evaluated as possible prognostic markers included tumour stage, Breslow thickness, patient gender, ulceration of the primary lesion, serum LDH, and site of distant metastases. Statistical analysis was performed using SPSS v19.0 for Windows. Publically available microarray expression data was analysed by means of FGA to indicate the genetic expression profile of melanoma cells. For the identification of genes and their function, the NCBI database was consulted. The 100 genes with the strongest association were filtered by hand for immune-related genes. Results – Median survival for female patients vs. male patients was resp. 106 and 93 weeks (p=0.015). Primary lesions occurred more frequently on the extremities in the female population, while they occurred more frequently on the torso in the male population. Survival analysis showed significant longer survival for patients with low serum LDH when compared to patients with high serum LDH (100 vs. 31 weeks, p<0.001). Metastases that indicate worse survival outcomes are CNS metastases, lung metastases, liver metastases and visceral metastases other than bone, skin or lymph node metastases. A list of 22.277 genes higly expressed by melanoma cells was created. Filtering by hand resulted in a total of 14 immune-related genes, of which four have not been associated with melanoma before. Conclusions – Biological and clinical markers that were found could predict patient survival and response to therapy at forehand could be used to create a risk profile for melanoma patients to select patients that apply for adjuvant therapy. Using FGA, fourteen immune-related genes, which are expressed in high quantity when compared to our control group were identified. These genes could provide useful markers for both patient survival and response to immune-therapy, and possibly even act as new targets for melanoma therapy. In the future, we hope to further validate the clinical value of these genes in a completed Frisian melanoma cohort.. Furthermore, FGA has provided a very resourceful database that can feed a broad line of future studies.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Supervisor: and Rijn, dr. R.S. van and Department of Oncology, MCL and Leeuwarden |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:55 |
| Last Modified: | 25 Jun 2020 10:55 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/1548 |
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