Radiation response in fibroblasts of long-term survivors of childhood cancer with and without second primary neoplasms

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.