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 | |
| State | Published - Oct 24 2015 |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
- Molecular Biology
- Molecular Medicine
Cite this
HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. / Teschendorff, Andrew E.; Lee, Shih Han; Jones, Allison; Fiegl, Heidi; Kalwa, Marie; Wagner, Wolfgang; Chindera, Kantaraja; Evans, Iona; Dubeau, Louis; Orjalo, Arturo; Horlings, Hugo M.; Niederreiter, Lukas; Kaser, Arthur; Yang, Winnie; Goode, Ellen L; Fridley, Brooke L.; Jenner, Richard G.; Berns, Els M J J; Wik, Elisabeth; Salvesen, Helga B.; Wisman, G. Bea A; van der Zee, Ate G J; Davidson, Ben; Trope, Claes G.; Lambrechts, Sandrina; Vergote, Ignace; Calvert, Hilary; Jacobs, Ian J.; Widschwendter, Martin.
In: Genome Medicine, Vol. 7, No. 1, 108, 24.10.2015.Research output: Contribution to journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=84945132239&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84945132239&partnerID=8YFLogxK
U2 - 10.1186/s13073-015-0233-4
DO - 10.1186/s13073-015-0233-4
M3 - Article
C2 - 26497652
AN - SCOPUS:84945132239
VL - 7
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 108
ER -