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Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation

BACKGROUND: Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased E...

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Autores principales: Grandt, Caine Lucas, Brackmann, Lara Kim, Foraita, Ronja, Schwarz, Heike, Hummel-Bartenschlager, Willempje, Hankeln, Thomas, Kraemer, Christiane, Zahnreich, Sebastian, Drees, Philipp, Mirsch, Johanna, Spix, Claudia, Blettner, Maria, Schmidberger, Heinz, Binder, Harald, Hess, Moritz, Galetzka, Danuta, Marini, Federico, Poplawski, Alicia, Marron, Manuela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061869/
https://www.ncbi.nlm.nih.gov/pubmed/36997855
http://dx.doi.org/10.1186/s10020-023-00629-2
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author Grandt, Caine Lucas
Brackmann, Lara Kim
Foraita, Ronja
Schwarz, Heike
Hummel-Bartenschlager, Willempje
Hankeln, Thomas
Kraemer, Christiane
Zahnreich, Sebastian
Drees, Philipp
Mirsch, Johanna
Spix, Claudia
Blettner, Maria
Schmidberger, Heinz
Binder, Harald
Hess, Moritz
Galetzka, Danuta
Marini, Federico
Poplawski, Alicia
Marron, Manuela
author_facet Grandt, Caine Lucas
Brackmann, Lara Kim
Foraita, Ronja
Schwarz, Heike
Hummel-Bartenschlager, Willempje
Hankeln, Thomas
Kraemer, Christiane
Zahnreich, Sebastian
Drees, Philipp
Mirsch, Johanna
Spix, Claudia
Blettner, Maria
Schmidberger, Heinz
Binder, Harald
Hess, Moritz
Galetzka, Danuta
Marini, Federico
Poplawski, Alicia
Marron, Manuela
author_sort Grandt, Caine Lucas
collection PubMed
description BACKGROUND: Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. METHODS: Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case–control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. RESULTS: We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. CONCLUSION: N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a deficiency could potentially lead to a higher vulnerability towards side effects of exposure to high doses of ionizing radiation, but following low-dose applications employed in diagnostics, as well. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00629-2.
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spelling pubmed-100618692023-03-31 Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation Grandt, Caine Lucas Brackmann, Lara Kim Foraita, Ronja Schwarz, Heike Hummel-Bartenschlager, Willempje Hankeln, Thomas Kraemer, Christiane Zahnreich, Sebastian Drees, Philipp Mirsch, Johanna Spix, Claudia Blettner, Maria Schmidberger, Heinz Binder, Harald Hess, Moritz Galetzka, Danuta Marini, Federico Poplawski, Alicia Marron, Manuela Mol Med Research Article BACKGROUND: Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. METHODS: Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case–control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. RESULTS: We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. CONCLUSION: N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a deficiency could potentially lead to a higher vulnerability towards side effects of exposure to high doses of ionizing radiation, but following low-dose applications employed in diagnostics, as well. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00629-2. BioMed Central 2023-03-30 /pmc/articles/PMC10061869/ /pubmed/36997855 http://dx.doi.org/10.1186/s10020-023-00629-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Grandt, Caine Lucas
Brackmann, Lara Kim
Foraita, Ronja
Schwarz, Heike
Hummel-Bartenschlager, Willempje
Hankeln, Thomas
Kraemer, Christiane
Zahnreich, Sebastian
Drees, Philipp
Mirsch, Johanna
Spix, Claudia
Blettner, Maria
Schmidberger, Heinz
Binder, Harald
Hess, Moritz
Galetzka, Danuta
Marini, Federico
Poplawski, Alicia
Marron, Manuela
Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation
title Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation
title_full Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation
title_fullStr Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation
title_full_unstemmed Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation
title_short Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation
title_sort gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061869/
https://www.ncbi.nlm.nih.gov/pubmed/36997855
http://dx.doi.org/10.1186/s10020-023-00629-2
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