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

Authors: Teschendorff, A. E.; Lee, S. H.; Jones, A.; Fiegl, H.; Kalwa, M.; Wagner, W.; Chindera, K.; Evans, I.; Dubeau, L.; Orjalo, A.; Horlings, H. M.; Niederreiter, L.; Kaser, A.; Yang, W.; Goode, E. L.; Fridley, B. L.; Jenner, R. G.; Berns, E. M. J. J.; Wik, E.; Salvesen, H. B.; Wisman, G. B. A.; van der Zee, A. G. J.; Davidson, B.; Tropé, C. G.; Lambrechts, S.; Vergote, I.; Calvert, H.; Jacobs, I. J.; Widschwendter, M.
Article Title: HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer
Abstract: Background: 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. Methods: 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. Results: 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 < 0.001) in the discovery and 1.63 (95 % CI 1.04-2.56; P = 0.032) in the validation set. This effect was not seen in patients who did not receive carboplatin (0.97 [95 % CI 0.52-1.80; P = 0.932]). HOTAIR expression or its surrogate DNAme signature predicted poor outcome in all additional sets of carboplatin-treated ovarian cancer patients while HOTAIR expressors responded preferentially to cisplatin (multivariate interaction P = 0.008). Conclusions: Non-coding RNA HOTAIR or its more stable DNAme surrogate may indicate the presence of a subset of cells which confer resistance to carboplatin and can serve as (1) a marker to personalise treatment and (2) a novel target to overcome carboplatin resistance. © 2015 Teschendorff et al.
Keywords: adult; cancer chemotherapy; cancer survival; controlled study; aged; major clinical study; cancer recurrence; cisplatin; cancer staging; outcome assessment; gene; mesenchyme cell; carboplatin; ovary cancer; gene expression; genetic association; cell differentiation; chemosensitivity; dna methylation; prediction; cancer mortality; cancer resistance; survival time; drug response; untranslated rna; receiver operating characteristic; human; female; priority journal; article; ic50; hotair gene
Journal Title: Genome Medicine
Volume: 7
ISSN: 1756-994X
Publisher: Biomed Central Ltd  
Date Published: 2015-10-24
Start Page: 108
Language: English
DOI: 10.1186/s13073-015-0233-4
PROVIDER: scopus
PMCID: PMC4619324
PUBMED: 26497652
Notes: Export Date: 2 December 2015 -- Source: Scopus
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  1. Shih-Han Lee
    6 Lee