Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma
| Autor: | Xiaolong Fan, Fan Wu, Chunsheng Kang, Yanfei Wei, Jing Feng, Zhengmin Cong, Wen Cheng, Kaikai Yi, Ayaz Ali Samo, Yunqiu Zhang, Qiong Yang, Tao Jiang, Jiuyi Li, Zheng Wang, Paolo Salomoni, Yu Huang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Genome instability genetics [Glioma] genetics [Biomarkers Tumor] Cdc20 Proteins biosynthesis [Neoplasm Proteins] pharmacology [Temozolomide] Mice Nude Biology Corrections metabolism [Glioma] Genomic Instability Transcriptome Mice Chromosome instability Glioma drug therapy [Glioma] Biomarkers Tumor Temozolomide medicine Animals Humans Progenitor cell Mitosis genetics [Neoplasm Proteins] Multidisciplinary Gene Expression Profiling biosynthesis [Biomarkers Tumor] Cell cycle medicine.disease Xenograft Model Antitumor Assays Neoplasm Proteins genetics [Cdc20 Proteins] Gene Expression Regulation Neoplastic CDC20 protein human Chemotherapy Adjuvant Tumor progression Cancer research Female ddc:500 pathology [Glioma] biosynthesis [Cdc20 Proteins] |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America 116(14), 6975-6984 (2019). doi:10.1073/pnas.1814060116 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Genomic instability (GI) drives tumor heterogeneity and promotes tumor progression and therapy resistance. However, causative factors underlying GI and means for clinical detection of GI in glioma are inadequately identified. We describe here that elevated expression of a gene module coexpressed with CDC20 (CDC20-M), the activator of the anaphase-promoting complex in the cell cycle, marks GI in glioma. The CDC20-M, containing 139 members involved in cell proliferation, DNA damage response, and chromosome segregation, was found to be consistently coexpressed in glioma transcriptomes. The coexpression of these genes was conserved across multiple species and organ systems, particularly in human neural stem and progenitor cells. CDC20-M expression was not correlated with the morphological subtypes, nor with the recently defined molecular subtypes of glioma. CDC20-M signature was an independent and robust predictor for poorer prognosis in over 1,000 patients from four large databases. Elevated CDC20-M signature enabled the identification of individual glioma samples with severe chromosome instability and mutation burden and of primary glioma cell lines with extensive mitotic errors leading to chromosome mis-segregation. AURKA, a core member of CDC20-M, was amplified in one-third of CDC20-M-high gliomas with gene-dosage-dependent expression. MLN8237, a Food and Drug Administration-approved AURKA inhibitor, selectively killed temozolomide-resistant primary glioma cells in vitro and prolonged the survival of a patient-derived xenograft mouse model with a high-CDC20-M signature. Our findings suggest that application of the CDC20-M signature may permit more selective use of adjuvant therapies for glioma patients and that dysregulated CDC20-M members may provide a therapeutic vulnerability in glioma. |
| Databáze: | OpenAIRE |
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