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

Manuela Marron; Lara Kim Brackmann; Heike Schwarz; Willempje Hummel-Bartenschlager; Sebastian Zahnreich; Danuta Galetzka; Iris Schmitt; Christian Grad; Philipp Drees; Johannes Hopf; Johanna Mirsch; Peter Scholz-Kreisel; Peter Kaatsch; Alicia Poplawski; Moritz Hess; Harald Binder; Thomas Hankeln; Maria Blettner; Heinz Schmidberger

doi:10.2196/32395

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 Res Protoc. 2021 Nov 11;10(11):e32395. doi: 10.2196/32395.

Authors

Manuela Marron¹, Lara Kim Brackmann¹, Heike Schwarz¹, Willempje Hummel-Bartenschlager¹, Sebastian Zahnreich², Danuta Galetzka², Iris Schmitt², Christian Grad², Philipp Drees³, Johannes Hopf³, Johanna Mirsch⁴, Peter Scholz-Kreisel⁵, Peter Kaatsch⁶, Alicia Poplawski⁵, Moritz Hess⁷, Harald Binder⁷, Thomas Hankeln⁸, Maria Blettner⁵, Heinz Schmidberger²

Affiliations

¹ Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany.
² Department of Radiation Oncology and Radiation Therapy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
³ Department of Orthopedics and Traumatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁴ Radiation Biology and DNA Repair, Technical University of Darmstadt, Darmstadt, Germany.
⁵ Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁶ German Childhood Cancer Registry, Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁷ Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
⁸ Institute of Organismic and Molecular Evolution, Molecular Genetics and Genome Analysis, Johannes Gutenberg University, Mainz, Germany.

PMID: 34762066
PMCID: PMC8663494
DOI: 10.2196/32395

Abstract

Background: Therapy for a first primary neoplasm (FPN) in childhood with high doses of ionizing radiation is an established risk factor for second primary neoplasms (SPN). An association between exposure to low doses and childhood cancer is also suggested; however, results are inconsistent. As only subgroups of children with FPNs develop SPNs, an interaction between radiation, genetic, and other risk factors is presumed to influence cancer development.

Objective: Therefore, the population-based, nested case-control study KiKme aims to identify differences in genetic predisposition and radiation response between childhood cancer survivors with and without SPNs as well as cancer-free controls.

Methods: We conducted a population-based, nested case-control study KiKme. Besides questionnaire information, skin biopsies and saliva samples are available. By measuring individual reactions to different exposures to radiation (eg, 0.05 and 2 Gray) in normal somatic cells of the same person, our design enables us to create several exposure scenarios for the same person simultaneously and measure several different molecular markers (eg, DNA, messenger RNA, long noncoding RNA, copy number variation).

Results: Since 2013, 101 of 247 invited SPN patients, 340 of 1729 invited FPN patients, and 150 of 246 invited cancer-free controls were recruited and matched by age and sex. Childhood cancer patients were additionally matched by tumor morphology, year of diagnosis, and age at diagnosis. Participants reported on lifestyle, socioeconomical, and anthropometric factors, as well as on medical radiation history, health, and family history of diseases (n=556). Primary human fibroblasts from skin biopsies of the participants were cultivated (n=499) and cryopreserved (n=3886). DNA was extracted from fibroblasts (n=488) and saliva (n=510).

Conclusions: This molecular-epidemiological study is the first to combine observational epidemiological research with standardized experimental components in primary human skin fibroblasts to identify genetic predispositions related to ionizing radiation in childhood and SPNs. In the future, fibroblasts of the participants will be used for standardized irradiation experiments, which will inform analysis of the case-control study and vice versa. Differences between participants will be identified using several molecular markers. With its innovative combination of experimental and observational components, this new study will provide valuable data to forward research on radiation-related risk factors in childhood cancer and SPNs.

International registered report identifier (irrid): DERR1-10.2196/32395.

Keywords: cell line; childhood cancer; feasibility; fibroblast; irradiation; neoplasm; participation; second cancer; second primary neoplasm; study design.

©Manuela Marron, Lara Kim Brackmann, Heike Schwarz, Willempje Hummel-Bartenschlager, Sebastian Zahnreich, Danuta Galetzka, Iris Schmitt, Christian Grad, Philipp Drees, Johannes Hopf, Johanna Mirsch, Peter Scholz-Kreisel, Peter Kaatsch, Alicia Poplawski, Moritz Hess, Harald Binder, Thomas Hankeln, Maria Blettner, Heinz Schmidberger. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.11.2021.