HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.
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.
Statistical Genomics Group, UCL Cancer Institute, University College London, London, UK. a.teschendorff@ucl.ac.uk.|CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. a.teschendorff@ucl.ac.uk.
Andrew E
AE
Teschendorff
Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. lees7@mskcc.org.|Sloan Kettering Institute, Cancer Biology & Genetics Program, New York, NY, USA. lees7@mskcc.org.
Shih-Han
SH
Lee
Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. allison.jones@ucl.ac.uk.
Allison
A
Jones
Department of Gynaecology and Obstetrics, Innsbruck Medical University, Innsbruck, Austria. heidelinde.fiegl@i-med.ac.at.
Heidi
H
Fiegl
Helmholtz-Institute for Biomedical Technology, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany. marie.kalwa@rwth-aachen.de.
Marie
M
Kalwa
Helmholtz-Institute for Biomedical Technology, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany. wwagner@ukaachen.de.
Wolfgang
W
Wagner
Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. k.chindera@ucl.ac.uk.
Kantaraja
K
Chindera
Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. iona.evans@ucl.ac.uk.
Iona
I
Evans
Department of Pathology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA. ldubeau@usc.edu.
Louis
L
Dubeau
Biosearch Technologies, Novato, CA, USA. aorjalo@gmail.com.
Arturo
A
Orjalo
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. hhorlings@bccrc.ca.
Hugo M
HM
Horlings
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. niederreiter.lukas@gmail.com.
Lukas
L
Niederreiter
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. ak729@cam.ac.uk.
Arthur
A
Kaser
Department of Molecular Oncology, British Columbia Cancer Agency Research Centre, Vancouver, Canada. WYang@bccancer.bc.ca.
Winnie
W
Yang
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA. egoode@mayo.edu.
Ellen L
EL
Goode
Biostatistics and Informatics Shared Resource, The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA. bfridley@kumc.edu.
Brooke L
BL
Fridley
UCL Division of Infection and Immunity, University College London, London, UK. r.jenner@ucl.ac.uk.
Richard G
RG
Jenner
Department of Medical Oncology, Erasmus MC-Cancer Center, Rotterdam, The Netherlands. p.berns@erasmusmc.nl.
Els M J J
EM
Berns
Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway. Elisabeth.Wik@k1.uib.no.|Department of Pathology, Haukeland University Hospital, Bergen, Norway. Elisabeth.Wik@k1.uib.no.
Elisabeth
E
Wik
Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway. helga.salvesen@k2.uib.no.
Helga B
HB
Salvesen
Department of Gynaecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. g.b.a.wisman@umcg.nl.
G Bea A
GB
Wisman
Department of Gynaecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. a.g.j.van.der.zee@umcg.nl.
Ate G J
AG
van der Zee
Division of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway. ben.davidson@ous-hf.no.
Ben
B
Davidson
Department of Gynaecological Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway. ctr@ous-hf.no.
Claes G
CG
Trope
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium. sandrina.lambrechts@uzleuven.be.
Sandrina
S
Lambrechts
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium. ignace.vergote@uzleuven.be.
Ignace
I
Vergote
Drug Development Group, UCL Cancer Institute, University College London, London, UK. hilary.calvert@ucl.ac.uk.
Hilary
H
Calvert
Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. i.jacobs@unsw.edu.au.|University of Manchester, Manchester, UK. i.jacobs@unsw.edu.au.|University of New South Wales, Sydney, Australia. i.jacobs@unsw.edu.au.
Ian J
IJ
Jacobs
Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. m.widschwendter@ucl.ac.uk.
Martin
M
Widschwendter
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D055815:Young Adult
D000970:Antineoplastic Agents; C561566:HOTAIR long untranslated RNA, human; D062085:RNA, Long Noncoding; D016190:Carboplatin