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

Andrew E. Teschendorff; Shih Han Lee; Allison Jones; Heidi Fiegl; Marie Kalwa; Wolfgang Wagner; Kantaraja Chindera; Iona Evans; Louis Dubeau; Arturo Orjalo; Hugo M. Horlings; Lukas Niederreiter; Arthur Kaser; Winnie Yang; Ellen L. Goode; Brooke L. Fridley; Richard G. Jenner; Els M.J.J. Berns; Elisabeth Wik; Helga B. Salvesen; G. Bea A. Wisman; Ate G.J. van der Zee; Ben Davidson; Claes G. Trope; Sandrina Lambrechts; Ignace Vergote; Hilary Calvert; Ian J. Jacobs; Martin Widschwendter

doi:10.1186/s13073-015-0233-4

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

Andrew E. Teschendorff, Shih Han Lee, Allison Jones, Heidi Fiegl, Marie Kalwa, Wolfgang Wagner, Kantaraja Chindera, Iona Evans, Louis Dubeau, Arturo Orjalo, Hugo M. Horlings, Lukas Niederreiter, Arthur Kaser, Winnie Yang, Ellen L. Goode, Brooke L. Fridley, Richard G. Jenner, Els M.J.J. Berns, Elisabeth Wik, Helga B. SalvesenG. Bea A. Wisman, Ate G.J. van der Zee, Ben Davidson, Claes G. Trope, Sandrina Lambrechts, Ignace Vergote, Hilary Calvert, Ian J. Jacobs, Martin Widschwendter

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

109 Scopus citations

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.

Original language	English (US)
Article number	108
Journal	Genome medicine
Volume	7
Issue number	1
DOIs	https://doi.org/10.1186/s13073-015-0233-4
State	Published - Oct 24 2015

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

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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., ... Widschwendter, M. (2015). HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. Genome medicine, 7(1), [108]. https://doi.org/10.1186/s13073-015-0233-4

Teschendorff, AE, Lee, SH, Jones, A, Fiegl, H, Kalwa, M, Wagner, W, Chindera, K, Evans, I, Dubeau, L, Orjalo, A, Horlings, HM, Niederreiter, L, Kaser, A, Yang, W, Goode, EL, Fridley, BL, Jenner, RG, Berns, EMJJ, Wik, E, Salvesen, HB, Wisman, GBA, van der Zee, AGJ, Davidson, B, Trope, CG, Lambrechts, S, Vergote, I, Calvert, H, Jacobs, IJ & Widschwendter, M 2015, 'HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer', Genome medicine, vol. 7, no. 1, 108. https://doi.org/10.1186/s13073-015-0233-4

@article{1f2b16ae5d424e19b3ae46c6f1f89446,

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.",

author = "Teschendorff, {Andrew E.} and Lee, {Shih Han} and Allison Jones and Heidi Fiegl and Marie Kalwa and Wolfgang Wagner and Kantaraja Chindera and Iona Evans and Louis Dubeau and Arturo Orjalo and Horlings, {Hugo M.} and Lukas Niederreiter and Arthur Kaser and Winnie Yang and Goode, {Ellen L.} and Fridley, {Brooke L.} and Jenner, {Richard G.} and Berns, {Els M.J.J.} and Elisabeth Wik and Salvesen, {Helga B.} and Wisman, {G. Bea A.} and {van der Zee}, {Ate G.J.} and Ben Davidson and Trope, {Claes G.} and Sandrina Lambrechts and Ignace Vergote and Hilary Calvert and Jacobs, {Ian J.} and Martin Widschwendter",

note = "Funding Information: The research leading to these results has received funding from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 305428 (Project EpiFemCare) and was strongly supported by funds from The Eve Appeal (http://www.eveappeal.org.uk/) and a grant from the UCLH/UCL Comprehensive Biomedical Research Center and was undertaken at UCLH/UCL, which received a proportion of its funding from the Department of Health NIHR Biomedical Research Centers funding scheme. A.E.T. was supported by a Heller Research Fellowship and by the Shanghai Institute for Biological Sciences/Chinese Academy of Sciences. R.G.J. was supported by a MRC Career Development Fellowship. H.B.S was supported by Helse Vest, Research Council of Norway and The Norwegian Cancer Society (Harald Andersens legacy). B.D. and C.G.T. were supported by the Inger and John Fredriksen Foundation for Ovarian Cancer Research. L.D. was supported by grant number RO1CA 133117 from the United States National Institutes of Health. H.M.H. is supported by a translational research fellowship from Dutch Cancer Society (KWF 2013-5869) This project was supported by the European Network Translational Research in Gynaecological Oncology (ENTRIGO) of the European Society of Gynaecological Oncology (ESGO). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2015 Teschendorff et al.",

year = "2015",

month = oct,

day = "24",

doi = "10.1186/s13073-015-0233-4",

language = "English (US)",

volume = "7",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer

AU - Teschendorff, Andrew E.

AU - Lee, Shih Han

AU - Jones, Allison

AU - Fiegl, Heidi

AU - Kalwa, Marie

AU - Wagner, Wolfgang

AU - Chindera, Kantaraja

AU - Evans, Iona

AU - Dubeau, Louis

AU - Orjalo, Arturo

AU - Horlings, Hugo M.

AU - Niederreiter, Lukas

AU - Kaser, Arthur

AU - Yang, Winnie

AU - Goode, Ellen L.

AU - Fridley, Brooke L.

AU - Jenner, Richard G.

AU - Berns, Els M.J.J.

AU - Wik, Elisabeth

AU - Salvesen, Helga B.

AU - Wisman, G. Bea A.

AU - van der Zee, Ate G.J.

AU - Davidson, Ben

AU - Trope, Claes G.

AU - Lambrechts, Sandrina

AU - Vergote, Ignace

AU - Calvert, Hilary

AU - Jacobs, Ian J.

AU - Widschwendter, Martin

N1 - Funding Information: The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 305428 (Project EpiFemCare) and was strongly supported by funds from The Eve Appeal (http://www.eveappeal.org.uk/) and a grant from the UCLH/UCL Comprehensive Biomedical Research Center and was undertaken at UCLH/UCL, which received a proportion of its funding from the Department of Health NIHR Biomedical Research Centers funding scheme. A.E.T. was supported by a Heller Research Fellowship and by the Shanghai Institute for Biological Sciences/Chinese Academy of Sciences. R.G.J. was supported by a MRC Career Development Fellowship. H.B.S was supported by Helse Vest, Research Council of Norway and The Norwegian Cancer Society (Harald Andersens legacy). B.D. and C.G.T. were supported by the Inger and John Fredriksen Foundation for Ovarian Cancer Research. L.D. was supported by grant number RO1CA 133117 from the United States National Institutes of Health. H.M.H. is supported by a translational research fellowship from Dutch Cancer Society (KWF 2013-5869) This project was supported by the European Network Translational Research in Gynaecological Oncology (ENTRIGO) of the European Society of Gynaecological Oncology (ESGO). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2015 Teschendorff et al.

PY - 2015/10/24

Y1 - 2015/10/24

N2 - 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.

AB - 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.

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U2 - 10.1186/s13073-015-0233-4

DO - 10.1186/s13073-015-0233-4

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JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

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ER -

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

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