Epigenetische Veränderungen an Genen des WNT/β-Catenin-Signalwegs in Wilms-Tumoren

Karst, Amei Katharina (2025): Epigenetische Veränderungen an Genen des WNT/β-Catenin-Signalwegs in Wilms-Tumoren. Dissertation, LMU München: Medizinische Fakultät

Abstract

WT represent the most common type of kidney tumors in children. Therefore, it should be given high priority in research. Overall, the prognosis of this disease is favourable, nevertheless most of the affected children suffer from the exhausting therapy, which almost always consists of surgery, neoadjuvant chemotherapy and sometimes even additional radiotherapy. Each of this therapeutic modalities causes different side effects and long-term effects, which, especially in children, should be considered carefully. This study focused on the WNT/β-Catenin-pathway, which is known to be dysregulated in some of WT and even in higher frequency in other tumors. Up to now, there is a lack of knowledge, regarding whether epigenetic changes are responsible for these dysregulations. As a starting point for this study, an investigation of an irregular activation of the WNT/β-Catenin-pathway was conducted for a cohort of 101 WT. An overexpression of AXIN2 was observed in 31 % of WT through a gene expression analysis, which accounts for a larger portion than previously reported. Thus, the relevance of the research question could be confirmed. One possible reason for this dysregulation could be the mutation of CTNNB1, which is already known as one of the most common mutations in WT. In the examined cohort, this mutation accounts only for 16 % of WT with activated WNT/β-Catenin-pathway. Therefore, as the next step, the involvement of APC, known to be altered in a lot of different tumors, was investigated as a potential cause of pathway-activation. This could not be confirmed through expression analysis or methylation analysis. Another focus was directed towards the group of SFRP. It could not be stated that there is a lower expression level for SFRP2,4,5, which could lead to an dysregulated activation of the WNT/β-Catenin-pathway. For SFRP1 the expression was significantly lower than in the control group, but the interpretation of these results is difficult as no connection could be established with the activation of the WNT/β-Catenin-pathway. Very few of WT with an underexpression of SRFP1 also showed an irregular activation of the WNT/β-Catenin-pathway. The cause of this significant underexpression of SFRP1 could not be identified. The methylation analysis in the promoter of SFRP1 did not show any changes compared to the healty kidney tissue. Further investigations are required therefore. According to previous research especially stromal WT are affected by an irregular activation of the WNT/β-Catenin-pathway in the investigated cohort. Other associations between an activation of the pathway and specific phenotypes, such as metastasis, tumor recurrence, age at diagnosis, gender, survival or bilateral occurrence could not be established. In summary this study could verify and underline the importance of interest in the WNT/β-Catenin-pathway in the origin of WT. The pathway is aberrant in a large portion of WT. In addition to CTNNB1 mutation, there have to be more mechanisms causing the proven activation of the pathway. Epigenetic changes in the genes investigated could not be attributed as the cause of the aberrant activation. A direct relationship between the underexpression of SFRP1 and the activation needs to be further investigated. Although WT with activation of the WNT/β-Catenin-pathway belong to the group of WT with favourable histology, it is worth further investigating these approaches. A detailed understanding of the origin of WT could be applied in clinical practice, for example to deescalate therapy or to provide a basis for future pharmacological treatments.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Wilms-Tumor, WNT/β-Catenin-Signalweg, Epigenetik, CTNNB1, SFRP
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Deutsch
• Datum der mündlichen Prüfung: 15. Mai 2025
• 1. Bericht­erstatter:in: Kappler, Roland