Molecular karyotyping and gene expression analysis in childhood cancer patients
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ORIGINAL ARTICLE
Molecular karyotyping and gene expression analysis in childhood cancer patients Galetzka Danuta 1 & Müller Tobias 2 & Dittrich Marcus 2 & Endres Miriam 1 & Kartal Nergiz 1 & Sinizyn Olesja 1 & Rapp Steffen 3,4 & Zeller Tanja 5,6 & Müller Christian 5,6 & Hankeln Thomas 3 & Scholz-Kreisel Peter 7 & Chorzempa Heather 8,9 & Mirsch Johanna 10 & Poplawski Alicia 7 & Rossmann Heidi 11 & Spix Claudia 12 & Haaf Thomas 9 & Prawitt Dirk 8 & Marron Manuela 13 & Schmidberger Heinz 1 Received: 6 November 2019 / Revised: 20 April 2020 / Accepted: 8 June 2020 # The Author(s) 2020
Abstract The genetic etiology of sporadic childhood cancer cases remains unclear. We recruited a cohort of 20 patients who survived a childhood malignancy and then developed a second primary cancer (2N), and 20 carefully matched patients who survived a childhood cancer without developing a second malignancy (1N). Twenty matched cancer-free (0N) and additional 1000 (0N) GHS participants served as controls. Aiming to identify new candidate loci for cancer predisposition, we compared the genomewide DNA copy number variations (CNV) with the RNA-expression data obtained after in vitro irradiation of primary fibroblasts. In 2N patients, we detected a total of 142 genes affected by CNV. A total of 53 genes of these were not altered in controls. Six genes (POLR3F, SEC23B, ZNF133, C16orf45, RRN3, and NTAN1) that we found to be overexpressed after irradiation were also duplicated in the genome of the 2N patients. For the 1N collective, 185 genes were affected by CNV and 38 of these genes were not altered in controls. Five genes (ZCWPW2, SYNCRIP, DHX30, DHRS4L2, and THSD1) were located in duplicated genomic regions and exhibited altered RNA expression after irradiation. One gene (ABCC6) was partially duplicated in one 1N and one 2N patient. Analysis of methylation levels of THSD1 and GSTT2 genes which were detected in duplicated regions and are frequently aberrantly methylated in cancer showed no changes in patient’s fibroblasts. In summary, we describe rare and radiation-sensitive genes affected by CNV in childhood sporadic cancer cases, which may have an impact on cancer development.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00109-020-01937-4) contains supplementary material, which is available to authorized users. * Galetzka Danuta [email protected]; http://www.unimedizinmainz.de/radioonkologie-und-strahlentherapie
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Dzhk (Deutsches Zentrum für Herzkreislauf-Forschung), Standort Hamburg, Lübeck, Kiel, Hamburg, Germany
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Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre, Mainz, Germany
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Department of Radiation Oncology and Radiation Therapy, University Medical Centre, Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany
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Center for Pediatrics and Adolescent Medicine, University Medical Centre, Mainz, Germany
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Bioinformatics Department, Julius Maximilians University, Würzburg, Germany
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