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Integrated and cross-species omics analyses identify the DNA damage response pathway as an important vulnerable pathway in aggressive neuroblastoma tumors

Katleen De Preter (UGent) , Anneleen Beckers (UGent) , Suzanne Vanhauwaert (UGent) , Annelies Fieuw (UGent) , Sara De Brouwer (UGent) , Pieter Mestdagh (UGent) , Jo Vandesompele (UGent) and Franki Speleman (UGent)
Author
Organization
Abstract
Introduction: The past decade several high throughput technologies have been developed that allow to profile cancer cells at global omics level. The big datasets generated on these new platforms can significantly help in generating a comprehensive view and understanding of the tumor biology and subsequently fuels studies on the development and implementation of new molecular targeted therapies. For neuroblastoma, a childhood tumor of the developing sympathetic nervous system, new insights on targetable driver genes are currently limited. Methods: We studied neuroblastoma oncogenesis through analysis of big omics datasets using different bio-informatics tools. Available datasets include transcriptomic and genomic profiles of large sets of human and mouse neuroblastoma tumors and cell lines. Using those data (1) we performed dynamic gene expression analysis during tumor initiation and formation in a MYCN driven mouse model, (2) designed and tested an embryonic stem cell (ESC) signature and (3) integrated DNA copy number and m(i)RNA expression data using the Conexic tool in order to identify new driver genes. Results: Most interestingly, these independent 3 data-mining approaches lead to the identification of a converging theme that can be attributed to tumor aggressiveness and which can serve as an important novel target for therapy, i.e. the DNA damage response pathway. First, master regulator analysis of genes involved in MYCN driven neuroblastoma formation identified the transcription factor FOXM1, an important DNA damage regulator. Second, analysis of a m(i)RNA expression ESC signature in data of more than 200 neuroblastoma tumors allowed us to mark a subgroup of neuroblastoma tumors with increased stem cell capabilities which matched with the most agressive subset of neuroblastoma tumors. Remarkably, the top list of coding genes that correlate with the ESC signature was dominated by genes implicated in DNA damage response, including the FOXM1 gene. Third, driver gene identification in aggressive neuroblastoma tumors using the Conexic tool pointed at 2 DNA repair genes that are both known to be regulated by FOXM1. Conclusions: Based on these data, we hypothesize that FOXM1 plays an important central role in the MYC(N) induced DNA damage response and predict that FOXM1 and its downstream DNA repair genes impact on chemotherapy resistance. Currently, we are testing the effect of treatment with a FOXM1 inhibitor on neuroblastoma chemo-resistance.

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MLA
De Preter, Katleen, et al. “Integrated and Cross-Species Omics Analyses Identify the DNA Damage Response Pathway as an Important Vulnerable Pathway in Aggressive Neuroblastoma Tumors.” Translation of the Cancer Genome, Abstracts, American Association for Cancer Research (AACR), 2015.
APA
De Preter, K., Beckers, A., Vanhauwaert, S., Fieuw, A., De Brouwer, S., Mestdagh, P., … Speleman, F. (2015). Integrated and cross-species omics analyses identify the DNA damage response pathway as an important vulnerable pathway in aggressive neuroblastoma tumors. Translation of the Cancer Genome, Abstracts. Presented at the Translation of the Cancer Genome, San Francisco, CA, USA.
Chicago author-date
De Preter, Katleen, Anneleen Beckers, Suzanne Vanhauwaert, Annelies Fieuw, Sara De Brouwer, Pieter Mestdagh, Jo Vandesompele, and Franki Speleman. 2015. “Integrated and Cross-Species Omics Analyses Identify the DNA Damage Response Pathway as an Important Vulnerable Pathway in Aggressive Neuroblastoma Tumors.” In Translation of the Cancer Genome, Abstracts. American Association for Cancer Research (AACR).
Chicago author-date (all authors)
De Preter, Katleen, Anneleen Beckers, Suzanne Vanhauwaert, Annelies Fieuw, Sara De Brouwer, Pieter Mestdagh, Jo Vandesompele, and Franki Speleman. 2015. “Integrated and Cross-Species Omics Analyses Identify the DNA Damage Response Pathway as an Important Vulnerable Pathway in Aggressive Neuroblastoma Tumors.” In Translation of the Cancer Genome, Abstracts. American Association for Cancer Research (AACR).
Vancouver
1.
De Preter K, Beckers A, Vanhauwaert S, Fieuw A, De Brouwer S, Mestdagh P, et al. Integrated and cross-species omics analyses identify the DNA damage response pathway as an important vulnerable pathway in aggressive neuroblastoma tumors. In: Translation of the Cancer Genome, Abstracts. American Association for Cancer Research (AACR); 2015.
IEEE
[1]
K. De Preter et al., “Integrated and cross-species omics analyses identify the DNA damage response pathway as an important vulnerable pathway in aggressive neuroblastoma tumors,” in Translation of the Cancer Genome, Abstracts, San Francisco, CA, USA, 2015.
@inproceedings{7177842,
  abstract     = {{Introduction: The past decade several high throughput technologies have been developed that allow to profile cancer cells at global omics level. The big datasets generated on these new platforms can significantly help in generating a comprehensive view and understanding of the tumor biology and subsequently fuels studies on the development and implementation of new molecular targeted therapies. For neuroblastoma, a childhood tumor of the developing sympathetic nervous system, new insights on targetable driver genes are currently limited.
Methods: We studied neuroblastoma oncogenesis through analysis of big omics datasets using different bio-informatics tools. Available datasets include transcriptomic and genomic profiles of large sets of human and mouse neuroblastoma tumors and cell lines. Using those data (1) we performed dynamic gene expression analysis during tumor initiation and formation in a MYCN driven mouse model, (2) designed and tested an embryonic stem cell (ESC) signature and (3) integrated DNA copy number and m(i)RNA expression data using the Conexic tool in order to identify new driver genes. 
Results: Most interestingly, these independent 3 data-mining approaches lead to the identification of a converging theme that can be attributed to tumor aggressiveness and which can serve as an important novel target for therapy, i.e. the DNA damage response pathway. First, master regulator analysis of genes involved in MYCN driven neuroblastoma formation identified the transcription factor FOXM1, an important DNA damage regulator. Second, analysis of a m(i)RNA expression ESC signature in data of more than 200 neuroblastoma tumors allowed us to mark a subgroup of neuroblastoma tumors with increased stem cell capabilities which matched with the most agressive subset of neuroblastoma tumors. Remarkably, the top list of coding genes that correlate with the ESC signature was dominated by genes implicated in DNA damage response, including the FOXM1 gene. Third, driver gene identification in aggressive neuroblastoma tumors using the Conexic tool pointed at 2 DNA repair genes that are both known to be regulated by FOXM1. 
Conclusions: Based on these data, we hypothesize that FOXM1 plays an important central role in the MYC(N) induced DNA damage response and predict that FOXM1 and its downstream DNA repair genes impact on chemotherapy resistance. Currently, we are testing the effect of treatment with a FOXM1 inhibitor on neuroblastoma chemo-resistance.}},
  author       = {{De Preter, Katleen and Beckers, Anneleen and Vanhauwaert, Suzanne and Fieuw, Annelies and De Brouwer, Sara and Mestdagh, Pieter and Vandesompele, Jo and Speleman, Franki}},
  booktitle    = {{Translation of the Cancer Genome, Abstracts}},
  language     = {{eng}},
  location     = {{San Francisco, CA, USA}},
  publisher    = {{American Association for Cancer Research (AACR)}},
  title        = {{Integrated and cross-species omics analyses identify the DNA damage response pathway as an important vulnerable pathway in aggressive neuroblastoma tumors}},
  year         = {{2015}},
}