Differentielle Methylierung von H3K27 in EZH2 positiven large cell neuroendokrinen Tumoren des Thymus
von Ella Marie Kurzen
Datum der mündl. Prüfung:2023-02-01
Betreuer:Prof. Dr. Philipp Ströbel
Gutachter:Prof. Dr. Philipp Ströbel
Gutachter:Prof. Dr. Heidi Hahn
EnglischNeuroendocrine thymic tumors represent only 0.4% of all neuroendocrine tumors and are thus very rare. Four subtypes are classified by the WHO. A high-grade subtype is the large cell neuroendocrine carcinoma, which is characterized by its high expression of enhancer zeste homolog 2. Enhancer zeste homolog 2 is an enzyme that can catalyze the methylation of the 27th lysine residue of histone three. In previous research on a new morphomolecular classification of neuroendocrine thymic tumors, it has been noticed that there were discrepancies between enhancer zeste homolog 2 and methylated histone in large cell neuroendocrine carcinoma. An explanation for this phenomenon should be found in the dissertation. Furthermore, in the new morphomolecular classification, another subtype was classified, namely NET-G3. NET-G3s strongly resemble large cell neuroendocrine carcinoma, but have no enhancer zeste homolog 2 marker and are not purely malignant. By the obtained results, among others, a better classification into NET-G3 or large cell neuroendocrine carcinoma should be possible. In order to explain the differential methylation of H3K27, different parameters that may influence methylation were investigated. For this purpose, Sanger sequencing of the genes encoding the 27th lysine residue of histone three and a subunit of polycomb repressive complex 2, embryonic ectoderm development, were sequenced to reveal possible mutations. No mutation was detectable in any of the examined preparations of neuroendocrine lung and thymic tumors. Furthermore, immunohistochemical staining of H3K27ac, the demethylase KDM6A, enhancer zeste homolog 2, and H3K27me3 was performed. Unfortunately, the stainings did not allow correlation of the different parameters examined, explaining the discrepancy between the occurring levels of enhancer zeste homolog 2 and H3K27me3 or allowing a better classification of NET-G3s. Presumably, the discrepancies are due, on the one hand, to the small patient collective, which is conditioned by the rarity of neuroendocrine thymic tumors. On the other hand, another variable that was not considered in the studies probably plays an important role. Metabolism, for example, may be responsible for varying activities of enhancer zeste homolog 2. However, it remains relevant to investigate enhancer zeste homolog 2 because it is highly elevated in different tumor types and in some cases tumor therapy in the form of enhancer zeste homolog 2 inhibitors may be appropriate.
Keywords: H3K27; EZH2; LCNECs; TNETs; NETs