Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma

Abstract

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.

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation

“…No IDH1 mutations were observed in two previous studies of nine and 17 grade II/III spinal cord astrocytomas [13,31]. Similarly, IDH1 mutations were also not observed in another study of 25 cases of 2016 WHO grade IV spinal cord glioma [38]. Here, we confirmed this finding in a larger cohort (n = 58) of spinal cord astrocytoma cases with different histological grades.…”

“…However, patients rarely benefit from adjuvant or neoadjuvant chemotherapy and radiation therapy [10,16]. This may be due to the low rate of MGMT promoter methylation in spinal cord gliomas [4,33,38]; this was also observed in our study. Moreover, MGMT promoter methylation was only identified in H3-wildtype gliomas.…”

“…In contrast, a separate study of 120 patients indicated that the H3 K27M mutation is only associated with a poor prognosis in infratentorial gliomas, but not in supratentorial gliomas [33]. Although the H3 K27M mutation appeared to be associated with poor survival rates for spinal cord gliomas (less than 30 cases, in which the H3 K27M mutation was identified in 50-60% of tumors) in these studies, another study on twenty-five 2016 WHO grade IV spinal cord gliomas (including 20 with the H3 K27M mutation) indicated that the H3 K27M mutation was associated with a better prognosis [38]. Thus, the prognostic value of the H3 K27M mutation for spinal cord glioma remains controversial.…”

“…Recent advances in molecular studies, including the identification of the IDH mutation, 1p/19q co-deletion, H3 K27M mutation, EGFR amplification, TERT promoter mutation, BRAF V600E mutation, MGMT promoter methylation, and others, have revolutionized the diagnosis, classification, and precision chemotherapy of gliomas [5,8,9,14,19,24]. However, compared to brain gliomas, previous studies on spinal cord gliomas have usually included less than 30 cases in a single report, and the molecular characteristics of spinal cord glioma (astrocytoma) are still largely unknown [6,21,27,33,38]. In the present study, we summarized the clinical and basic molecular pathological characteristics of 83 patients with spinal cord astrocytomas, thus revealing the prognostic value of the BRAF V600E and TERT promoter mutations in grade II and III gliomas.…”

“…Currently, our understating of spinal cord astrocytomas is largely based on advances in their intracranial counterparts, as the low incidence of spinal cord astrocytomas leads to difficulties in collecting sufficient samples to run adequate analyses. However, genetic alterations and the molecular biological profile of spinal cord gliomas seem to be distinct from those of their brain counterparts [1,2,13,27,33,34,37,38].…”