Dataset Information

HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.

ABSTRACT: Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients' lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-coding RNA HOTAIR (HOX transcript antisense intergenic RNA) is involved in mesenchymal stem cell fate and cancer biology.We analyzed HOTAIR expression and associated surrogate DNA methylation (DNAme) in 134 primary ovarian cancer cases (63 received carboplatin, 55 received cisplatin and 16 no chemotherapy). We validated our findings by HOTAIR expression and DNAme analysis in a multicentre setting of five additional sets, encompassing 946 ovarian cancers. Chemo-sensitivity has been assessed in cell culture experiments.HOTAIR expression was significantly associated with poor survival in carboplatin-treated patients with adjusted hazard ratios for death of 3.64 (95 % confidence interval [CI] 1.78-7.42; P?

SUBMITTER: Teschendorff AE

PROVIDER: S-EPMC4619324 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.

Teschendorff Andrew E AE Lee Shih-Han SH Jones Allison A Fiegl Heidi H Kalwa Marie M Wagner Wolfgang W Chindera Kantaraja K Evans Iona I Dubeau Louis L Orjalo Arturo A Horlings Hugo M HM Niederreiter Lukas L Kaser Arthur A Yang Winnie W Goode Ellen L EL Fridley Brooke L BL Jenner Richard G RG Berns Els M J J EM Wik Elisabeth E Salvesen Helga B HB Wisman G Bea A GB van der Zee Ate G J AG Davidson Ben B Trope Claes G CG Lambrechts Sandrina S Vergote Ignace I Calvert Hilary H Jacobs Ian J IJ Widschwendter Martin M

Genome medicine 20151024

<h4>Background</h4>Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients' lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-coding RNA HOTAIR (HOX transcript antisense intergenic RNA) is involved in mesenchymal stem cell fate and cancer biology.<h4>Methods</h4>We analyzed HOTAIR expression and associated surroga ...[more]

PMID: 26497652

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed.MethodsHere, we employed patient-derived xenografts (PDXs) to detect predictive methylation biomarkers for platin-based therapies. We used MeDIP-Seq to generate genome-wide DNA methylation profiles of 22 PDXs, their parental primary NSCLC, and their corresponding normal tissues and complemented the data with gene expression analyses of the same tissues. Candidate biomarkers were validated with quantitative methylation-specific PCRs (qMSP) in an independent cohort.ResultsComprehensive analyses revealed that differential methylation patterns are highly similar, enriched in PDXs and lung tumor-specific when comparing differences in methylation between PDXs versus primary NSCLC. We identified a set of 40 candidate regions with methylation correlated to carboplatin response and corresponding inverse gene expression pattern even before therapy. This analysis led to the identification of a promoter CpG island methylation of LDL receptor-related protein 12 (LRP12) associated with increased resistance to carboplatin. Validation in an independent patient cohort (n = 35) confirmed that LRP12 methylation status is predictive for therapeutic response of NSCLC patients to platin therapy with a sensitivity of 80% and a specificity of 84% (p < 0.01). Similarly, we find a shorter survival time for patients with LRP12 hypermethylation in the TCGA data set for NSCLC (lung adenocarcinoma).ConclusionsUsing an epigenome-wide sequencing approach, we find differential methylation patterns from primary lung cancer and PDX-derived cancers to be very similar, albeit with a lower degree of differential methylation in primary tumors. We identify LRP12 DNA methylation as a powerful predictive marker for carboplatin resistance. These findings outline a platform for the identification of epigenetic therapy resistance biomarkers based on PDX NSCLC models.

Dataset Information

HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.

Publications

HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.

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