Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma

Abstract

Glioblastoma is the most frequently occurring and invariably fatal primary brain tumor in adults. The vast majority of glioblastomas is characterized by chromosomal copy number alterations, including gain of whole chromosome 7 and loss of whole chromosome 10. Gain of whole chromosome 7 is an early event in gliomagenesis that occurs in proneural-like precursor cells, which give rise to all isocitrate dehydrogenase (IDH) wild-type glioblastoma transcriptional subtypes. () is one gene on chromosome 7 known to drive gliomagenesis, but, given its location near the end of 7p, there are likely several other genes located along chromosome 7 that select for its increased whole-chromosome copy number within glioblastoma cells. To identify other potential genes that could select for gain of whole chromosome 7, we developed an unbiased bioinformatics approach that identified () as a gene whose expression correlated with gain of chromosome 7 and a more aggressive phenotype of the resulting glioma. High expression of in glioblastoma was associated with a proneural gene expression pattern and decreased overall survival in both human proneural and PDGF-driven mouse glioblastoma. Furthermore, overexpression promoted cellular proliferation and potentiated radioresistance. We also found enrichment of expression in recurrent human and mouse glioblastoma at first recurrence after radiotherapy. Overall, this study implicates as a chromosome 7-associated gene-level locus that promotes selection for gain of whole chromosome 7 and an aggressive phenotype in glioblastoma.

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

“…Similarly, HOXD9 was highly expressed in the Three genes from the HOXA cluster have also been reported to have an important role in resistance to therapy. Specifically, HOXA9 and HOXA10 have been associated with decreased sensitivity to the chemotherapy drug temozolomide (TMZ) in GBM patients, a finding that was further supported by a causal relationship in cell lines [169,124,150], and HOXA5 also decreased sensitivity to radiotherapy in vitro and in vivo [149].…”

“…The genetic manipulation of HOXA5, A9, A10, A13, B3, B7, B9, C6, C9, C10, and D9 showed that their expression increases the viability of GBM cell lines [151,154,152,149,146,153,161,157,156,150,126,165,122], and five of them (HOXA9, A13, C6, C10, and D9) also reduce cell death [122,146,156,150,126,151]. HOXA7, A9, B7, B9, C9, and C10 also increased GBM cell lines migration capacity [166,152,153,157,156,150,165], while HOXA6, A13, B3, and B13 promoted increased invasion [166,152,153,157,167,156,150,151,165,146].…”

“…In vivo, three genes of the "nine paralogues", HOXA9, HOXB9, and HOXC9, were shown to promote oncogenesis, as shown by the increased tumour volumes in subcutaneous GBM mouse models [153,150,165]. In clinically more relevant orthotopic models (i.e., based on intracranial implantation of GBM cells in mice), HOXA5, A9, A10, A13, C6, and C9 expression increased the GBM-associated death rate [146,161,150,165,154,149]. Particularly interesting in these orthotopic models was HOXA9 and HOXA5, which increased the resistance to TMZ-based chemotherapy and radiotherapy, respectively, as indicated by the lower overall survival (OS) of mice bearing tumours positive for these HOX genes, as compared to negative tumours [150].…”

“…The functional impact of approximately half of HOX genes in GBM has already been described, particularly concerning the HOXA cluster. This stronger emphasis in HOXA genes could be partly explained due to the fact that they are on chromosome 7, which is frequently amplified in GBM, although HOXA gene copy number alterations have not been consistently associated with its expression [122,150,149,161]. Future studies on the roles of the other HOX genes in glioma will be critical to provide a more complete picture of their implication in these tumours.…”

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

“…Among the 100 CpG sites with the largest radiation-induced difference in methylation, three sites in the gene SHROOM3, encoding for the actin-binding protein and cell morphology regulator, were identified (Additional file 1: Table S1). The Sphingosine-1-Phosphate Transporter (SP1) gene MFSD2B, a regulator of self-renewal and differentiation in neural and cancer progenitor cells [19], was also differentially methylated at multiple CpG sites (n = 6). Other genes with many altered sites included the glial fibrillary acidic protein GFAP, which encodes one of the major intermediate filament proteins of mature astrocytes, and the glutathione metabolism gene GSTP1.…”