Surgery (RMH) - Theses
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ItemKey clinical and molecular determinants of biological behavior in glioma: examining the role of the Salvador-Warts-Hippo pathway in glioma stem cells( 2011)Analysis of a landmark genetic sequencing project, identifying likely damaging genetic variants in a series of twenty-one glioma stem cells, reveals the Salvador-Wart-Hippo (SWH) pathway to be a key deregulated pathway. A constitutive tumour suppressor pathway, its down-stream effector yes-associated protein, or “YAP”, is implicated in regulating stem cell and progenitor cell self-renewal. We found that YAP is overexpressed in a group of selected glioma stem cells, in contrast to normal brain, and established glioma cell lines. When we compared YAP and constitutive phosphorylated- YAP (p-YAP) expression between the glioma stem cells and their matched bulk tumours, we found p-YAP was consistently more highly expressed in the bulk “parent” tumour, compared to the corresponding stem cell. These findings are consistent with YAP expression being a molecular marker of “stemness”. YAP expression was shown to correlate with an aggressive phenotype within our stem cell series, with respect to adverse survival outcomes and biological behavior. Tumours associated with YAPexpressing stem cells had worse overall survival than their non-YAP-expressing counterparts (median survival 8 months versus 15 months, HR 1.886, 95% CI 0.224 to 0.8413, p value 0.4727). This favorably contrasts with the only other related published translational research to date, showing that lack of YAP expression in gliomas carries a survival advantage. Within a selected cohort of glioma stem cells, YAP-expression correlated with increased proliferative capacity, assessed by LDH assay. We show new and novel evidence that YAP is an oncogene in glioma, and may be a key glioma stem cell marker, further adding to a shift towards re-conceptualizing high-grade glioma as a disease of molecular-genetic aberrations.