Abstract 4261: Cancer in childhood and molecular epidemiology - The KIKME case-control study

Abstract

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 a case-control study with 600 anticipated participants 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 in irradiated cultured human fibroblasts from skin biopsies. In a first step, we examine the participation proportions of survivors of childhood cancer with and without a SN and cancer free control patients (CO) from the department of accident surgery and orthopaedics. 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 will be 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, we estimate gene expression differences by RNA-Seq in fibroblasts after low (0.05 Gy) and high (2 Gy) radiation doses at different time points (0.25 h, 2 h, 24 h). In the first recruitment drives of the ongoing study, we recruited 77 patients with SN and 95 matched patients with only one PN from 1975 eligible former childhood cancer patients at the German Childhood Cancer Registry, as well as 22 CO patients. Until November 2016, 33% of the contacted 231 SN patients, 20% of the 486 contacted PN patients and 69% of the 32 contacted CO patients participated in our study. Two hours after low and high in vitro radiation doses, the largest number of genes were differentially expressed, some of them only after high doses, some only after low doses and some after both. 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 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. Citation Format: Manuela Marron, Sebastian Zahnreich, Olesja Sinizyn, Heinz Schmidberger, Moritz Hess, Patricia Sadre Dadras, Iris Altebockwinkel, Thomas Hankeln, Steffen Rapp, Anne Ebersberger, Christian Grad, Eva Holzhäuser, Lukas Eckhard, Dirk Proschek, Maria Blettner, Peter Kaatsch, Claudia Spix, Danuta Galetzka, Harald Binder. Cancer in childhood and molecular epidemiology - The KIKME case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4261. doi:10.1158/1538-7445.AM2017-4261

Hypermethylation of RAD9A intron 2 in childhood cancer patients and tumor cell lines

“…Moreover, fibroblasts of 20 matched, cancer-free individuals served as controls (0N). [69]. Twenty matched patients (sex and age) without cancer from the Department of Accident Surgery and Orthopedics served as controls (0N).…”