Intrinsic radiation sensitivity: Identification of biological and epidemiological long-term effects; Subproject C with the case-control study ‘Cancer in childhood and molecular epidemiology’
Description
- Radiation and chemotherapy of primary neoplasms are the only established risk factors for sequelae neoplasms after childhood cancer. In addition, some observational studies indicate an association between ionizing radiation and cancer risk, especially when radiation exposure occurred in childhood. Since the causes for the development of childhood cancers are still largely unclear and genetic factors are suspected to play a major role in the pathogenesis of childhood and young adult cancers, the main objective of the case-control study KiKme (principal investigator: Manuela Marron) was the genome-wide identification of genes involved in radiation response in former childhood cancer patients and cancer-free controls. The nearly 600 study participants were divided into three groups of subjects (phenotypes). In addition to the group of controls without cancer, the group of former childhood cancer patients is subdivided into subjects with only one primary neoplasia and subjects with additional independent sequelae. To identify radiation-associated genetic differences between survivors of childhood cancers with and without sequelae and cancer-free controls, irradiation experiments with high and low radiation doses were performed on their fibroblasts. The results of the irradiation experiments were supplemented by extensive questionnaire information on socioeconomic status, lifestyle, and health status of the participants, including medical diagnosis and therapy received. In addition, to investigate the occurrence of cancer in the family environment and to be able to epidemiologically quantify the associated familial background risk for any cancer, serious diseases in the family were queried.
The KiKme study did not find an increased risk of childhood cancer due to cancer cases in the family or in familial subgroups. However, cancer cases in the female relatives were associated with an increased risk of developing sequelae. The results of the questionnaire analyses also showed that the study participants were able to provide valid information on the cancer therapies they had received. With the help of the collected cancer therapy data, it could be shown that the receipt of chemotherapies was associated with an increased risk of health-related late sequelae (thyroid disease and lipid metabolism disorders). Concomitantly, childhood cancer survivors took more medications than healthy controls. Having lived through childhood cancer also showed lifestyle effects: while survivors had healthier lifestyles overall than healthy controls, they appeared to be less physically active than these same controls, but this could be explained by their overall higher disease burden.
Our previous results of radiation experiments indicate that the skin cells of former childhood cancer patients with second neoplasms respond inadequately and more defectively to mutagenic cancer therapies mimicked in our laboratory experiments. This could promote the development of a second tumor in affected patients after effective tumor therapy. However, since the skin cells of the participants were obtained retrospectively after the onset and treatment of the second tumor, we currently cannot exclude the influence of a second cancer therapy on these different reactions. Therefore, we are currently planning further studies to confirm our results but also to provide new insights and clinical indicators to offer future pediatric cancer patients the best possible therapy, medical care and quality of life.
The KiKme study was conducted within the ISIBELA consortium (http://www.unimedizin-mainz.de/isibela/startseite/willkommen.html) in Bremen (subproject C). The close cooperation of four partners of the ISIBELA consortium from different disciplines in Germany enables the implementation of various biological and epidemiological radiation research projects on the risk of childhood cancers as well as on long-term consequences of cancer therapies. The ISIBELA consortium was funded by the Federal Ministry of Education and Research (BMBF) as part of the "Grundlagenforschung Energie 2020+" concept as well as by the Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety
Funding period
- Begin: September 2015
End: August 2021
Sponsor
- Federal Ministry of Education and Research
Contact
Selected project-related publications
- Brackmann K, Foraita R, Schwarz H, Poplawski A, Hankeln T, Galetzka D, Zahnreich S, Spix C, Blettner M, Schmidberger H, Marron M. Self-administered questionnaire assessing childhood cancer treatments and associated risks for adverse health outcomes - The KiKme study. Frontiers in Oncology. 2023;13:1150629.
https://doi.org/10.3389/fonc.2023.1150629 - Grandt CL, Brackmann K, Foraita R, Schwarz H, Hummel-Bartenschlager W, Hankeln T, Kraemer C, Zahnreich S, Drees P, Mirsch J, Spix C, Blettner M, Schmidberger H, Binder H, Hess M, Galetzka D, Marini F, Poplawski A, Marron M. Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation. Molecular Medicine. 2023;29:41.
https://doi.org/10.1186/s10020-023-00629-2 - Grandt CL, Brackmann K, Poplawski A, Schwarz H, Marini F, Hankeln T, Galetzka D, Zahnreich S, Mirsch J, Spix C, Blettner M, Schmidberger H, Marron M. Identification of lncRNAs involved in response to ionizing radiation in fibroblasts of long-term survivors of childhood cancer and cancer-free controls. Frontiers in Oncology. 2023;13:1158176.
https://dx.doi.org/10.3389/fonc.2023.1158176 - Brackmann K, Foraita R, Schwarz H, Galetzka D, Zahnreich S, Hankeln T, Löbrich M, Poplawski A, Grabow D, Blettner M, Schmidberger H, Marron M. Late health effects and changes in lifestyle factors after cancer in childhood with and without subsequent second primary cancers - The KiKme case-control study. Frontiers in Oncology. 2022;12:1037276.
https://doi.org/10.3389/fonc.2022.1037276 - Galetzka D, Böck J, Wagner L, Dittrich M, Sinizyn O, Ludwig M, Rossmann H, Spix C, Radsak M, Scholz-Kreisel P, Mirsch J, Linke M, Brenner W, Marron M, Poplawski A, Haaf T, Schmidberger H, Prawitt D. Hypermethylation of RAD9A intron 2 in childhood cancer patients, leukemia and tumor cell lines suggest a role for oncogenic transformation. EXCLI Journal. 2022;21:117-143.
https://doi.org/10.17179/excli2021-4482 - Grandt CL, Brackmann K, Poplawski A, Schwarz H, Hummel-Bartenschlager W, Hankeln T, Kraemer C, Marini F, Zahnreich S, Schmitt I, Drees P, Mirsch J, Grabow D, Schmidberger H, Binder H, Hess M, Galetzka D, Marron M. Radiation-response in primary fibroblasts of long-term survivors of childhood cancer with and without second primary neoplasms: The KiKme study. Molecular Medicine. 2022;28:105.
https://doi.org/10.1186/s10020-022-00520-6 - Marron M, Brackmann K, Schwarz H, Hummel-Bartenschlager W, Zahnreich S, Galetzka D, Schmitt I, Grad C, Drees P, Hopf J, Mirsch J, Scholz-Kreisel P, Kaatsch P, Poplawski A, Hess M, Binder H, Hankeln T, Blettner M, Schmidberger H. Identification of genetic predispositions related to ionizing radiation in primary human skin fibroblasts from survivors of childhood and second primary cancer as well as cancer-free controls: Protocol for the nested case-control study KiKme. JMIR Research Protocols. 2021;10(11):e32395.
https://doi.org/10.2196/32395 - Brackmann K, Poplawski A, Grandt CL, Schwarz H, Hankeln T, Rapp S, Zahnreich S, Galetzka D, Schmitt I, Grad C, Eckhard L, Mirsch J, Blettner M, Scholz-Kreisel P, Hess M, Binder H, Schmidberger H, Marron M. Comparison of time and dose dependent gene expression and affected pathways in primary human fibroblasts after exposure to ionizing radiation. Molecular Medicine. 2020;26:85.
https://doi.org/10.1186/s10020-020-00203-0 - Scholz-Kreisel P, Kaatsch P, Spix C, Schmidberger H, Marron M, Grabow D, Becker C, Blettner M. Second malignancies following childhood cancer treatment in Germany from 1980 to 2014: A registry-based analysis. Deutsches Ärzteblatt International. 2018;115(23):385-392.
https://doi.org/10.3238/arztebl.2018.0385