Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Koeller, M.
Biomarkers in Melanoma Patients Treated with Immune-Checkpoint Inhibitors
Evaluation of Mismatch Repair Deficiency, Microsatellite Status and Total Mutation Load and Their Relationship with Prognosis and Treatment Response.
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2020. pp. 110
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Aigelsreiter Ariane
- Richtig Erika
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- Abstract:
- Scientific Background The occurrence of severe adverse events and high expenses in the immune checkpoint inhibitor (:= ICI) treatment of malignant melanoma (:= MM) prompts the necessity of reliable biomarkers for the clinical practice. The rate of mutations per mega base (:= mut/Mb) is a viable ICI-biomarker in MM. An increase of novel mutations due to defective mismatch repair (:= dMMR) occurs in MM mouse models and dMMR has been observed in MM patients benefitting from ICI. Methods Patients: MM patients (cutaneous, unknown primary) treated with ICI between 2012-2016 at the Department of Dermatology of the Medical University of Graz. Archived tissues samples were investigated using: dMMR: Immunohistochemistry (MLH1, MSH2, MSH6 and PMS2) in 23, polymerase chain reaction-based microsatellite fragment length analysis assay in 5 patients; mut/Mb: Oncomine TML Assay (Thermo Scientific) in 14 patients, grouped into a clinical benefit (n = 6) and a clinical non-benefit group (n = 7) (:= CBG, non-CBG, respectively). Results No loss of protein staining was detected (0% (0/23) CI: 0.00 – 14.81%). A microsatellite stable phenotype was observed in all tumors (100% (5/5)), with 40 % (2/5) showing loss of heterozygosity at the Pent-D locus. The mut/Mb was significantly higher in MM of the CBG (one-sided Wilcoxon test: p-value = 0.03671, n = 13). The mut/Mb was a feasible predictive biomarker (Receiver Operative Curve: Area under the curve = 0.810 (CI 0.561 – 1.00), Cut-Off = Youden’s J 9.51 [mut/Mb] (100 % sensitivity, 57.1 % specificity)). No correlation between the mut/Mb and the percentage of positively stained cells was found. A significant difference in the percentage of MLH1-positively stained tumor cells between the CBG and non-CBG (two-sided Wilcoxon test: p-value = 0.00168, n = 14) was found. Conclusion We infer from the literature and our findings that dMMR: -occurs in a small subset of MM treated with ICI, -plays a minor role in the pathogenesis of MMs with increased mut/Mb; Our study validates the use of the TML-assay as a predictive ICI-biomarker in MM. The observed relationship between the percentage of MLH1-positive tumor cells and treatment outcome should be validated by further studies.