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Intrinsic radiation sensitivity: identification of biological and epidemiological long-term effects (ISIBELA); Subproject C with the case-control study ‘Cancer in childhood and molecular epidemiology (KiKme)’

Description

Treatment of first primary neoplasms (PN) in childhood with radiotherapy or chemotherapy is an established risk factor for second primary neoplasms (SN). In addition, there is growing evidence for this association from observational studies on ionizing radiation and cancer risk, in particular after radiation exposure in childhood. As only a subgroup of the treated children suffers from SN, other risk modifying factors (e.g. genetics) must be involved. We are conducting the KiKme case-control study on cancer in childhood and molecular epidemiology with 600 anticipated participants (principal investigator: Manuela Marron). This study aims to evaluate gene-radiation interactions and risk of SN (leukemia, thyroid or skin cancer) as well as PN (leukemia, lymphoma or CNS) with a new epidemiological design, in which we combine observational with experimental elements by analyzing gene expression at the same time with and without irradiation in cultured human fibroblasts from skin biopsies.

The work package 2 of the ISIBELA consortium (http://www.unimedizin-mainz.de/isibela/startseite/willkommen.html) in Bremen (subproject C) includes the design and lead of the KiKme case-control study as well as the genome wide analysis of gen-radiation interactions and the risk of childhood cancer. The ISIBELA consortium is a collaboration of four research groups in Germany leading different biological and epidemiological projects on radiation exposure and risk of childhood cancer as well as long-term effects of cancer therapies. The German Federal Ministry of Education and Research (BMBF) and the Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) are funding this project within the Basic Energy Research 2020+ program from 2015 to 2018. The working package 2 has four objectives: (1) the design and implementation of the KiKme study, (2) the scientific leadership and coordination of the genome wide identification of genes and gen-radiation interaction on DNA and RNA level, (3) the analysis of further KiKme study data (e.g. family history of diseases), and (4) the responsibility for the multiple pseudonymization of all samples and results for each partner of the consortium.

In a first step, the participation proportions are examined in survivors of childhood cancer with and without a SN and in cancer free control patients (CO) from the department of accident surgery and orthopedics. In addition to a skin biopsy of 3 mm and a saliva sample, we collect detailed questionnaire information on lifetime exposure to medical radiation and chemotherapy, socio-demographic factors, smoking, drinking, physical activity, medical history and family history of cancer and other diseases. Cases and controls are matched by sex and age (1:1), and additionally among the former childhood cancer patients by type of the PN and year of first diagnosis (1 SN:3 PN). In explorative pilot experiments, gene expression differences were estimated by RNA-Seq in fibroblasts after low (0.05 Gy, 0.10 Gy) and high (2 Gy) radiation doses at different time points (0.25 h, 2 h, 24 h). To our knowledge, the KIKME study is the first epidemiological project analyzing differential gene expression in primary fibroblasts before and after radiation with high and low doses to evaluate the potential genetic basis for emergence of a SN and a PN. However, the biological importance of the suggested differential gene expression after high and low doses of radiation of the pilot experiments has to be confirmed with the full study population. In addition, the gene expression must be analyzed in detail by group (SN, PN, CO) and will be combined with results from whole genome sequencing in order to obtain a comprehensive view of the role of radiation in the carcinogenesis of childhood cancer.

Funding period

Begin:   September 2015
End:   April 2021

Sponsor

  • Federal Ministry of Education and Research

Contact

Dr. phil. Manuela Marron

Cooperation

  • Prof. Dr. Harald Binder (Institut für medizinische Biometrie, Epidemiologie und Informatik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz)
  • Prof. Dr. Maria Blettner (Institut für medizinische Biometrie, Epidemiologie und Informatik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz)
  • Prof. Dr. Philipp Drees (Zentrum für Orthopädie und Unfallchirurgie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz)
  • Prof. Dr. Tom Hankeln (Institut für Molekulargenetik, gentechnologische Sicherheitsforschung und Beratung, Johannes Gutenberg-Universität Mainz)
  • Prof. Dr. Markus Löbrich (Institut für Strahlenbiologie und DNA-Reparatur, Technische Universität Darmstadt)
  • Prof. Dr. Heinz Schmidberger (Klinik und Poliklinik für Radioonkologie undStrahlentherapie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz)

Selected project-related publications

    Presentations at scientific meetings/conferences

  • Marron M, Blettner M, Binder H, Hoffmann I, Kaatsch P, Disque-Kaiser U, Zahnreich S, Schmidberger H, Proschek D, Deckbar D, Naumann S, Weimer RN, Löbrich M, Galetzka D, Spix C. Cancer in childhood and molecular epidemiology - The CICME nested case-control study. 10. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi), 30. September-2. Oktober 2015, Potsdam.