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. 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^*

^*Corresponding author for this work

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

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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
Article number	108
Number of pages	12
Journal	Genome medicine
Volume	7
DOIs	https://doi.org/10.1186/s13073-015-0233-4
Publication status	Published - 24-Oct-2015

Keywords

PLATINUM-BASED CHEMOTHERAPY
EPITHELIAL-MESENCHYMAL TRANSITION
EMBRYONIC STEM-CELLS
ONCOLOGY-GROUP
SQUAMOUS CARCINOMA
UTERINE CERVIX
NONCODING RNAS
PHASE-II
GENES
TRIAL

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Additional file 3: of HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer
Orjalo, A. (Contributor), Widschwendter, M. (Contributor), Wagner, W. (Contributor), Wisman, B. (Contributor), Davidson, B. (Contributor), Vergote, I. (Contributor), Teschendorff, A. E. (Contributor), Calvert, H. (Contributor), Jenner, R. G. (Contributor), Wik, E. (Contributor), Chindera, K. (Contributor), Yang, W. (Contributor), Kalwa, M. (Contributor), Lambrechts, S. (Contributor), Salvesen, H. B. (Contributor), Fiegl, H. (Contributor), Berns, E. M. J. J. (Contributor), Jones, A. (Contributor), Trope, C. G. (Contributor), Horlings, H. M. (Contributor), Lee, S.-H. (Contributor), Fridley, B. L. (Contributor), Evans, I. (Contributor), Kaser, A. (Contributor), Niederreiter, L. (Contributor), van der Zee, A. (Contributor), Dubeau, L. (Contributor), Jacobs, I. J. (Contributor) & Goode, E. L. (Contributor), University of Groningen, 24-Oct-2015
DOI: 10.6084/m9.figshare.c.3639527_d13.v1, https://doi.org/10.6084%2Fm9.figshare.c.3639527_d13.v1
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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, Article 108. https://doi.org/10.1186/s13073-015-0233-4

@article{59ff4fd0cf2e43c88e28baf4425ac708,

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.",

keywords = "PLATINUM-BASED CHEMOTHERAPY, EPITHELIAL-MESENCHYMAL TRANSITION, EMBRYONIC STEM-CELLS, ONCOLOGY-GROUP, SQUAMOUS CARCINOMA, UTERINE CERVIX, NONCODING RNAS, PHASE-II, GENES, TRIAL",

author = "Teschendorff, \{Andrew E.\} and Shih-Han Lee 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",

year = "2015",

month = oct,

day = "24",

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

language = "English",

volume = "7",

journal = "Genome medicine",

issn = "1756-994X",

publisher = "BMC",

}

Teschendorff, AE, Lee, S-H, 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, 108. https://doi.org/10.1186/s13073-015-0233-4

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

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.

KW - PLATINUM-BASED CHEMOTHERAPY

KW - EPITHELIAL-MESENCHYMAL TRANSITION

KW - EMBRYONIC STEM-CELLS

KW - ONCOLOGY-GROUP

KW - SQUAMOUS CARCINOMA

KW - UTERINE CERVIX

KW - NONCODING RNAS

KW - PHASE-II

KW - GENES

KW - TRIAL

U2 - 10.1186/s13073-015-0233-4

DO - 10.1186/s13073-015-0233-4

M3 - Article

SN - 1756-994X

VL - 7

JO - Genome medicine

JF - Genome medicine

M1 - 108

ER -

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

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Keywords

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Additional file 3: of HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer

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