Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients

Chen C, Bartenhagen C, Gombert M, Okpanyi V, Binder V, Röttgers S, Bradtke J, Teigler-Schlegel A, Harbott J, Ginzel S, Thiele R, et al. (2015)
Leukemia research.

Journal Article | Published | English

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Abstract
: 20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18). In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways.
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Chen C, Bartenhagen C, Gombert M, et al. Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients. Leukemia research. 2015.
Chen, C., Bartenhagen, C., Gombert, M., Okpanyi, V., Binder, V., Röttgers, S., Bradtke, J., et al. (2015). Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients. Leukemia research.
Chen, C., Bartenhagen, C., Gombert, M., Okpanyi, V., Binder, V., Röttgers, S., Bradtke, J., Teigler-Schlegel, A., Harbott, J., Ginzel, S., et al. (2015). Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients. Leukemia research.
Chen, C., et al., 2015. Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients. Leukemia research.
C. Chen, et al., “Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients”, Leukemia research, 2015.
Chen, C., Bartenhagen, C., Gombert, M., Okpanyi, V., Binder, V., Röttgers, S., Bradtke, J., Teigler-Schlegel, A., Harbott, J., Ginzel, S., Thiele, R., Husemann, P., Krell, P., Borkhardt, A., Dugas, M., Hu, J., Fischer, U.: Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients. Leukemia research. (2015).
Chen, Cai, Bartenhagen, Christoph, Gombert, Michael, Okpanyi, Vera, Binder, Vera, Röttgers, Silja, Bradtke, Jutta, Teigler-Schlegel, Andrea, Harbott, Jochen, Ginzel, Sebastian, Thiele, Ralf, Husemann, Peter, Krell, Pina, Borkhardt, Arndt, Dugas, Martin, Hu, Jianda, and Fischer, Ute. “Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients”. Leukemia research (2015).
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PMID: 26189108
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