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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s13073-015-0233-4) contains supplementary material, which is available to authorized users.

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