lmproving diagnosis of central nervous system tumours using genetic and epigenetic tools
Brain tumor diagnostics has traditionally been based on histopathology stains. The introduction of immunohistochemistry stains resulted in improved ability to classify these often devastating tumors. The understanding of molecular markers in central nervous system tumors has improved substantially in recent decades. Demonstration of specific genetic changes such as mutations can have crucial impact on selection of therapy. Genetic changes also play an increasingly important role when it comes to classification of these tumors. Correct classification and grading are important to be able to give correct prognostic and predictive information and are of fundamental importance for efficient clinical patient handling. In this thesis, we use several molecular techniques to improve tumor diagnosis and tumor classification and investigate the utility of these methods to give a deeper understanding of these neoplastic processes. In Paper I, we investigated the DNA methylation profiling method for molecular classification of diffuse lower grade gliomas. We showed that DNA methylation profiling not only gave correct diagnostic and prognostic information but also were able to give reliable molecular information enabling molecular classification of the tumors according to the World Health Organization classification system. In Paper II, we assessed changes in DNA methylation pattern over time in diffuse IDH-mutant gliomas. We showed that tumors accumulated methylation alterations during progression, but that the overall methylation patterns most often were maintained upon recurrence. In Paper III, we explored if a proposed immunohistochemistry-based investigation of phenotype predicted survival and tumor recurrence in a clinical cohort of diffuse low-grade gliomas that were reclassified according to the 2021 WHO criteria. In Paper IV, we describe a 16-month-old patient with a tumor in the third ventricle with a relapse two years after diagnosis. The tumor was initially classified as a low-grade glioma but was after methylation profiling reclassified as an infant-type hemispheric glioma. To search for druggable targets and for further refinement of the molecular background both whole genome sequencing and whole transcriptome sequencing were performed. A novel TPR::ROS1 fusion gene was detected activating the MAPK-, PI3K- and JAK/STAT- pathways. In Paper V, we present a cystic pilocytic astrocytoma with KIAA1549::BRAF fusion in a 16-year-old patient. The tumor showed ganglion cell morphology and different vascularization in a nodular component. With extended molecular examination we were able to prove that the cells with ganglion cell morphology were of neoplastic origin. In conclusion, we further demonstrate the importance of adding molecular investigation in the histopathological diagnostic work-up. We also present arguments for the importance of evaluating molecular findings in correlation with the histomorphology picture.
Parts of work
I. Ferreyra Vega S, Olsson Bontell T, Corell A, Smits A, Jakola AS, Carén H. DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas. Clin Epigenetics 2021:13(1):102. PMID: 33941250 PMCID: PMC8091784 ::doi::10.1186/s13148-021-01085-7II. Ferreyra Vega S, Olsson Bontell T, Teresia K, Jakola AS, Carén H. Longitudinal DNA methylation analysis of adult-type IDH-mutant gliomas. Acta Neuropathologica Communications 2023:11(1):23. PMID: 36739454 PMCID: PMC9899392 ::doi::10.1186/s40478-023-01520-1III. Dénes A*, Olsson Bontell T*, Barchéus H, Ferreya Vega S, Carén H, Lindskog C, Jakola AS, Smits A. The Clinical value of proneural, classical and mesenchymal protein signatures in WHO 2021 adult-type diffuse lower-grade gliomas. Manuscript submitted. *Shared first author.IV. Deland L, Keane S, Olsson Bontell T, Fagman H, Sjögren H, Lind AE, Carén H, Tisell M, Nilsson JA, Ejeskär K, Sabel M, Abel F. Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma. Cancer Genomics Proteomics 2022:19(6):711-726. PMID: 36316040 PMCID: PMC9620451 ::doi::10.21873/cgp.20354V. Olsson Bontell T, Danielsson A, Dahr N, Deland L, Tisell M, Sjögren H, Sabel M, Carén H, Abel F. Formation of ganglion cells in a nodular component of a cystic infratentorial pilocytic astrocytoma carrying KIAA1549::BRAF fusion. Manuscript.
Doctor of Philosophy (Medicine)
University of Gothenburg. Sahlgrenska Academy
Institute of Neuroscience and Physiology. Department of Physiology
Fredagen den 2 juni 2023, kl 13.00, Hörsal Åke Göransson, Medicinaregatan 11, Göteborg https://gu-se.zoom.us/j/61789098524?pwd=eC93Tng5YW93OTU5Szl4dXlnUnZTQT09
Date of defence
Olsson Bontell, Thomas
DNA methylation profiling
DNA methylation-based classification
Diffuse lower grade-glioma