Abstract 3839: Investigation of epigenetic based inter-tumoral heterogeneity identifies novel ZMIZ1 gene as a biomarker of cancer patient survival in multiple tumor types

Abstract

Abstract Glioblastoma is the most malignant primary brain tumor and is universally fatal despite the use of the best treatment available. However a small percentage of these patients live considerably longer. Extensive genetic and epigenetic analysis has identified IDH1 mutation, G-CIMP (Glioma-CpG Island Methylator Phenotype) phenotype and MGMT as markers of better survival in glioblastoma. These markers though can only be associated with a small fraction of long term survivors (defined as glioblastoma patients surviving >3 years), underlying the need for better biomarkers of improved survival. Epigenetic analysis of inter-tumoral heterogeneity in the TCGA glioblastoma cohort identified a truncated form of the novel ZMZI1 gene to be associated with improved survival in patients hypermethylated in the alternative promoter of the truncated ZMIZ1 form, in an independent manner from IDH1, G-CIMP or MGMT methylation status. A validation cohort of 31 glioblastoma long term survivors with low prevalence of the known markers IDH1, G-CIMP and MGMT showed that ZMIZ1 methylation was positive in 42% of the patients, more sensitive and specific than IDH1, G-CIMP or MGMT. Extending our analysis to lower grade gliomas as well as other central nervous system tumors showed that higher methylation of the truncated ZMIZ1 was predicting a more favorable outcome in astrocytomas but not in oligodendrogliomas. Furthermore, in non-CNS tumors including breast cancer, colorectal cancer, bladder cancer and renal cell carcinoma, lower expression of the truncated ZMIZ1 form predicted a favorable survival, statistically significant in univariate and multivariate analysis adjusting for tumor stage and grade. In vitro loss of function and gain of function studies showed that ZMIZ1 is significantly affecting migration of glioblastoma cell lines, leaving unaffected the proliferation capacity of these cells. Loss of function studies showed that decreased ZMIZ1 expression in glioblastoma is resulting in higher sensitivity of glioblastoma cells to temozolamide. These results identify a novel pan-cancer biomarker of prognosis as well as a new gene that could potentially play a key role in cancer pathogenesis and resistance to treatment. Interestingly, unlike many other key cancer genes ZMIZ1 expression is regulated via epigenetic rather than genetic alterations in the entirety of human cancers. Citation Format: Dimitrios Mathios, Taeyoung Hwang, Jillian Phallen, Chetan Bettewgoda, Patrick Ha, Peter Burger, Henry Brem, Kerrie McDonald, Chul-Kee Park, Michael Lim. Investigation of epigenetic based inter-tumoral heterogeneity identifies novel ZMIZ1 gene as a biomarker of cancer patient survival in multiple tumor types. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3839. doi:10.1158/1538-7445.AM2015-3839