Validation of prognostic biomarkers for overall survival in melanoma patients undergoing autologous vaccination

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Author
Ayyıldız, Zeynep Özge
Advisor
Güre, Ali Osmay
Date
2014Publisher
Bilkent University
Language
English
Type
Thesis
Metadata
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http://hdl.handle.net/11693/30008Abstract
Malignant Melanoma is deadliest type of skin cancer, seen with low frequency. Lack of
diagnostic and prognostic markers are important obstacles during early detection and selection
of appropriate adjuvant therapy for malignant melanoma patients. Upon early diagnosis of
melanoma in patients with stage IA and IB, the survival rates for 5 to 10 years is above 85%
based on American Cancer Society statistics. However, with increasing stage and low survival
rates, selection of appropriate post surgical adjuvant therapy has high impact to increase the
survival and life quality of patients. Immunotherapy trials targeting malignant melanoma
(MM) patients have been developing in larger extents in the last 2 decades, considering
melanoma is the most immugenic cancer type among all cancers. Based on these facts, we
decided to search for prognostic biomarkers which will guide clinicians to define appropriate
malignant melanoma patients to apply autologous vaccination as a post surgical adjuvant
therapy. With the contribution of our collaborator research group, we were able to obtain 28
primary cell cultures of MM patients with known survival outcomes, and their gene
expression profiles in Luminex platform. Grounding from the results of Unsupervised
Survival Analysis Tool (USAT; a software designed to determine prognosis-associated
mRNAs, developed in our laboratory), we decided to validate the expression profiles of
prospective prognostic biomarker genes in the primary cell culture samples, with qRT-PCR.
Subsequent to elimination of samples determined as being altered in culture over time, and
thus no longer representing their expression profile, based on Sum of Absolute Rank
Difference (SARD) analysis, 8 genes validated out of 10 in 21 samples were as follows; CT
genes (SSX1, MAGEA1), EMT markers (CDX2, CLDN1), DNA repair genes (ERCC1,
LIG3), transforming growth factor alpha (TGFα), A-kinase anchor protein 13 (AKAP13).
Previous studies of our laboratory, concerning high immunogenic potential of CT genes in
cancers, made SSX1 and MAGEA1 our major interest in autologous vaccinated MM patients.
Our findings suggest that autologous vaccination might increase overall survival especially in
malignant melanoma patients whose tumors show higher CT gene expression. We show that
high expression of TGFα can also be used as a prognostic marker for identifying patients who
will benefit from this treatment.