E-GEOD-22865 - CHAC1 mRNA expression is a strong prognostic biomarker in breast and ovarian cancer
Released on 1 December 2011, last updated on 26 June 2012
Extracellular, cancer-specific methylated DNA has been shown to be a prognostic marker when detected in serum or plasma. In this study we investigated the effect of treating cancer cells with differentially methylated CpG DNA. When breast cancer cell lines were treated with methylated CpG DNA, a consistent upregulation of CHAC1 mRNA expression was observed. CHAC1 was recently described to be a novel component of the unfolded protein response pathway. To elucidate the role of CHAC1 mRNA expression in cancer in more detail, we analyzed expression of this gene in breast (n=107) and ovarian cancer (n=107) and found a strong correlation with tumor differentiation. Poorly differentiated tumors exhibited higher CHAC1 expression levels (p=0.004 for breast and p=0.031 for ovarian cancer). Additionally, hormone receptor (HR)-negative breast cancers (p<0.001) and advanced stage disease ovarian cancers (p=0.026) also demonstrated high CHAC1 mRNA levels. mRNA expression analysis of the two known CHAC1 isoforms showed a strong association of expression above the median with poor outcome in breast cancer patients in a multivariate analysis (isoform a: relative risk (RR) of death 3.2 (95% CI 1.6-6.5; p<0.01); RR of relapse 3.9 (95% CI 1.6-9.8; p<0.01); isoform b: relative risk (RR) of death 3.5 (95% CI 1.6-7.3; p<0.01); RR of relapse 6.6 (95% CI 2.4-18.5; p<0.01)). Univariate analysis in ovarian cancer showed that CHAC1 mRNA expression above the median was associated with a poor relapse free survival (p=0.03). In younger ovarian cancer patients (age < median age), a high CHAC1 mRNA expression was associated with overall survival (p=0.007) and relapse free survival (p=0.015). Finally, we show that downregulation of CHAC1 by small interfering RNA suppressed breast cancer cell migration and proliferation, whereas overexpression resulted in an observed increase in these cellular behaviours. This is the first report demonstrating that a gene (CHAC1) whose expression is triggered by methylated, but not unmethylated DNA, is involved in tumour biology. Human breast cancer cell lines (BT-20, Hs578T) were treated with methylated and unmethylated DNA oligos, and differentially expressed genes were identified between treatments with methylated and un-methylated oligos.
transcription profiling by array
Johannes Rainer <email@example.com>, Alexander M Strasak, Allison Jones, Daniel Egle, Elisabeth Müller-Holzner, Elisabeth Presul, Georg Goebel, Heidi Fiegl, Ian J Jacobs, Martin Widschwendter, Regina Berger, Stefan Lang, Stephan Schmidt
Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients. Goebel G, Berger R, Strasak AM, Egle D, Müller-Holzner E, Schmidt S, Rainer J, Presul E, Parson W, Lang S, Jones A, Widschwendter M, Fiegl H. , Europe PMC 22108517