Stopsack Konrad H.
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Stopsack Konrad H.
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Item-typ:Veröffentlichung, Radiation response in fibroblasts of long-term survivors of childhood cancer with and without second primary neoplasms(2025-07-07); ; The past decade has brought an increase in long-term survival of childhood cancer, accompanied by a rise in second primary cancers later in life. Despite active research efforts the causes for secondary primary neoplasms in childhood cancer survivors remain unclear. High penetrance mutations and anti-cancer cytostatics can explain some, but not all cases. A dysfunctional cellular radiation response may explain further cases as a response to radiation therapy against the first cancer entity. Therefore, the aim of this dissertation was to expand the role of the radiation response in second neoplasms of childhood cancer survivors. Thus, we measured radiation-induced transcriptomic changes in a large (N=156, n=52 per group) collective of sampled human fibroblasts as part of the nested case-control study KiKme. Here, the transcriptome in fibroblasts of cancer-free controls, long-term survivors of childhood cancer with and without second primary neoplasms was measured using RNASeq and compared after exposure to a low (0.05 Gray) or a high (2 Gray) radiation dose. The groupwise differences and variability in expression, as well as subsequent functional implications were identified using established and novel bioinformatic pipelines. There were two key findings after exposure to 0.05 Gray. First, the degree of p53 signaling pathway-activity ranged from most in controls to least active in survivors with second primary neoplasms. Second, the latter showed abnormalities in the cell fate decision, potentially indicating an impaired functioning. Genomic damages may not be removed by the cell, accumulate, and drive carcinogenesis. Another highlight of this work was the identification of the lncRNAs AL109976.1 and AL158206.1 to be markedly upregulated and functionally involved in the radiation response post-2 Gray. In future efforts, these may be potent targets for modulating tumor radiation sensitivity. Additionally, the interplay of the identified key players with further OMICs levels needs to be investigated next. Such efforts may help identifying patients at risk for immediate adverse reactions to ionizing radiation.Dissertation28 26