Abstract
Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.
Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.
Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years.
Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
| Original language | English |
|---|---|
| Pages (from-to) | 1240-1250 |
| Number of pages | 11 |
| Journal | Annals of Oncology |
| Volume | 31 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 1 Sept 2020 |
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In: Annals of Oncology, Vol. 31, No. 9, 01.09.2020, p. 1240-1250.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Prognostic gene expression signature for high-grade serous ovarian cancer
AU - AOCS Group
AU - Millstein, J.
AU - Budden, T.
AU - Goode, E. L.
AU - Anglesio, M. S.
AU - Talhouk, A.
AU - Intermaggio, M. P.
AU - Leong, H. S.
AU - Chen, S.
AU - Elatre, W.
AU - Gilks, B.
AU - Nazeran, T.
AU - Volchek, M.
AU - Bentley, R. C.
AU - Wang, C.
AU - Chiu, D. S.
AU - Kommoss, S.
AU - Leung, S. C.Y.
AU - Senz, J.
AU - Lum, A.
AU - Chow, V.
AU - Sudderuddin, H.
AU - Mackenzie, R.
AU - George, J.
AU - Bowtell, D. D.
AU - Chenevix-Trench, G.
AU - Green, A.
AU - Webb, P.
AU - deFazio, A.
AU - Gertig, D.
AU - Traficante, N.
AU - Fereday, S.
AU - Moore, S.
AU - Hung, J.
AU - Harrap, K.
AU - Sadkowsky, T.
AU - Pandeya, N.
AU - Malt, M.
AU - Mellon, A.
AU - Robertson, R.
AU - Vanden Bergh, T.
AU - Jones, M.
AU - Mackenzie, P.
AU - Maidens, J.
AU - Nattress, K.
AU - Chiew, Y. E.
AU - Stenlake, A.
AU - Sullivan, H.
AU - Alexander, B.
AU - Ashover, P.
AU - Brown, S.
AU - Corrish, T.
AU - Green, L.
AU - Jackman, L.
AU - Ferguson, K.
AU - Martin, K.
AU - Martyn, A.
AU - Ranieri, B.
AU - White, J.
AU - Jayde, V.
AU - Mamers, P.
AU - Bowes, L.
AU - Galletta, L.
AU - Giles, D.
AU - Hendley, J.
AU - Alsop, K.
AU - Schmidt, T.
AU - Shirley, H.
AU - Ball, C.
AU - Young, C.
AU - Viduka, S.
AU - Tran, Hoa
AU - Bilic, Sanela
AU - Glavinas, Lydia
AU - Brooks, Julia
AU - Stuart-Harris, R.
AU - Kirsten, F.
AU - Rutovitz, J.
AU - Clingan, P.
AU - Glasgow, A.
AU - Proietto, A.
AU - Braye, S.
AU - Otton, G.
AU - Shannon, J.
AU - Bonaventura, T.
AU - Stewart, J.
AU - Begbie, S.
AU - Friedlander, M.
AU - Bell, D.
AU - Baron-Hay, S.
AU - Ferrier,a, A.
AU - Gard, G.
AU - Nevell, D.
AU - Pavlakis, N.
AU - Valmadre, S.
AU - Young, B.
AU - Camaris, C.
AU - Crouch, R.
AU - Edwards, L.
AU - Hacker, N.
AU - Marsden, D.
AU - Robertson, G.
AU - Beale, P.
AU - Beith, J.
AU - Carter, J.
AU - Dalrymple, C.
AU - Houghton, R.
AU - Russell, P.
AU - Links, M.
AU - Grygiel, J.
AU - Hill, J.
AU - Brand, A.
AU - Byth, K.
AU - Jaworski, R.
AU - Sharma, R.
AU - Wain, G.
AU - Ward, B.
AU - Papadimos, D.
AU - Crandon, A.
AU - Cummings, M.
AU - Horwood, K.
AU - Obermair, A.
AU - Perrin, L.
AU - Wyld, D.
AU - Nicklin, J.
AU - Davy, M.
AU - Oehler, M. K.
AU - Hall, C.
AU - Dodd, T.
AU - Healy, T.
AU - Pittman, K.
AU - Henderson, D.
AU - Miller, J.
AU - Pierdes, J.
AU - Blomfield, P.
AU - Challis, D.
AU - McIntosh, R.
AU - Parker, A.
AU - Brown, B.
AU - Rome, R.
AU - Allen, D.
AU - Grant, P.
AU - Hyde, S.
AU - Laurie, R.
AU - Robbie, M.
AU - Healy, D.
AU - Jobling, T.
AU - Manolitsas, T.
AU - McNealage, J.
AU - Rogers, P.
AU - Susil, B.
AU - Sumithran, E.
AU - Simpson, I.
AU - Phillips, K.
AU - Rischin, D.
AU - Fox, S.
AU - Johnson, D.
AU - Lade, S.
AU - Loughrey, M.
AU - O'Callaghan, N.
AU - Murray, W.
AU - Waring, P.
AU - Billson, V.
AU - Pyman, J.
AU - Neesham, D.
AU - Quinn, M.
AU - Underhill, C.
AU - Bell, R.
AU - Ng, L. F.
AU - Blum, R.
AU - Ganju, V.
AU - Hammond, I.
AU - Leung, Y.
AU - McCartney, A.
AU - Buck, M.
AU - Haviv, I.
AU - Purdie, D.
AU - Whiteman, D.
AU - Zeps, N.
AU - Steed, H.
AU - Koziak, J. M.
AU - Köbel, M.
AU - McNeish, I. A.
AU - Goranova, T.
AU - Ennis, D.
AU - Macintyre, G.
AU - Silva De Silva, D.
AU - Ramón y Cajal, T.
AU - García-Donas, J.
AU - Hernando Polo, S.
AU - Rodriguez, G. C.
AU - Cushing-Haugen, K. L.
AU - Harris, H. R.
AU - Greene, C. S.
AU - Zelaya, R. A.
AU - Behrens, S.
AU - Fortner, R. T.
AU - Sinn, P.
AU - Herpel, E.
AU - Lester, J.
AU - Lubiński, J.
AU - Oszurek, O.
AU - Tołoczko, A.
AU - Cybulski, C.
AU - Menkiszak, J.
AU - Pearce, C. L.
AU - Pike, M. C.
AU - Tseng, C.
AU - Alsop, J.
AU - Rhenius, V.
AU - Song, H.
AU - Jimenez-Linan, M.
AU - Piskorz, A. M.
AU - Gentry-Maharaj, A.
AU - Karpinskyj, C.
AU - Widschwendter, M.
AU - Singh, N.
AU - Kennedy, C. J.
AU - Harnett, P. R.
AU - Gao, B.
AU - Johnatty, S. E.
AU - Sayer, R.
AU - Boros, J.
AU - Winham, S. J.
AU - Keeney, G. L.
AU - Kaufmann, S. H.
AU - Larson, M. C.
AU - Luk, H.
AU - Hernandez, B. Y.
AU - Thompson, P. J.
AU - Wilkens, L. R.
AU - Carney, M. E.
AU - Trabert, B.
AU - Lissowska, J.
AU - Brinton, L.
AU - Sherman, M. E.
AU - Bodelon, C.
AU - Hinsley, S.
AU - Lewsley, L. A.
AU - Glasspool, R.
AU - Banerjee, S. N.
AU - Stronach, E. A.
AU - Haluska, P.
AU - Ray-Coquard, I.
AU - Mahner, S.
AU - Winterhoff, B.
AU - Slamon, D.
AU - Levine, D. A.
AU - Brown, R.
AU - Henderson, M. J.
AU - Doherty, J. A.
N1 - Funding Information: This work was funded by the National Institutes of Health/National Cancer Institute (NCI) Grants to SJR [grant number R01CA172404 ] and J.A. Doherty and MAR [grant number R01CA168758 ], the Canadian Institutes for Health Research (Proof-of-Principle I program, no grant number applicable) and the United States Department of Defense Ovarian Cancer Research Program [grant number OC110433 ]. J. Millstein and SJR received support from National Institutes of Health / National Cancer Institute [grant number P30CA014089 ] and J. Millstein received support from NIH/National Cancer Institute award number P01CA196569. MSA receives funding from the Janet D. Cottrelle Foundation Scholar's program managed by the BC Cancer Foundation (no grant number applicable). JG was partially supported by the National Institutes of Health / National Cancer Institute [grant number P30CA034196 ]. CW was a Career Enhancement Awardee of the Mayo Clinic SPORE in Ovarian Cancer [grant number P50 CA136393 ]. MJH received funding from Cancer Australia (1067110), DGH receives support from the Dr Chew Wei Memorial Professorship in Gynecologic Oncology , (no grant number applicable) the Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology, no grant number applicable), and the Janet D. Cottrelle Foundation (no grant number applicable). MW receives funding from the European Union's Horizon 2020 European Research Council Programme [grant number H2020 BRCA-ERC ] under Grant Agreement No. 742432 , as well as from the charity The Eve Appeal ( https://eveappeal.org.uk/ , no grant number applicable) and support from the National Institute for Health Research (NIHR, no grant number applicable) and the University College London Hospitals (UCLH) Biomedical Research Centre (no grant number applicable). GEK is supported by the Miriam and Sheldon Adelson Medical Research Foundation (no grant number applicable). BYK is funded by the American Cancer Society Early Detection Professorship [grant number SIOP-06-258-01-COUN ] and the National Center for Advancing Translational Sciences (NCATS) [grant number UL1TR000124 ]. HRH is supported by the National Institutes of Health / National Cancer Institute [grant number K22 CA193860 ]. OVCARE (including the VAN study) receives core funding through the BC Cancer Foundation (no grant number applicable) and The VGH+UBC Hospital Foundation (authors AT, BG, DGH and MSA, no grant number applicable). The AOV study is supported by the Canadian Institutes of Health Research [grant number MOP-86727 ]. The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling [grant numbers ID 310670 , ID 628903 ] and the Cancer Institute NSW [grant numbers ID 12/RIG/1-17 , 15/RIG/1-16 ]. The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command [grant number DAMD17-01-1-0729 ], The Cancer Council Victoria , Queensland Cancer Fund , The Cancer Council New South Wales , The Cancer Council South Australia , The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia [grant numbers NHMRC, ID199600 , ID400413 , ID400281 ]. BriTROC-1 was funded by Ovarian Cancer Action (to IAM and JDB) [grant number 006 ] and supported by Cancer Research UK [grant numbers A15973 , A15601 , A18072 , A17197 , A19274 , A19694 ] and the National Institute for Health Research Cambridge and Imperial Biomedical Research Centres (no grant number applicable). SEARCH was supported by Cancer Research UK [grant number A16561 ]. The University of Cambridge receives salary support for PDPP from the NHS Clinical Academic Reserve (no grant number applicable). Samples from the Mayo Clinic were collected and provided with support of the National Institutes of Health/National Cancer Institute (NCI) P50 CA136393 (ELG, GLK, SHK, MES). S. Orsulic was funded by the Department of Defense Award W81XWH-17-1-0144. MRC Clinical Trials Unit at UCL receives funding from The Eve Appeal (The Oak Foundation) with investigators supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and MRC core funding (MR_UU_12023). Funding Information: We thank all the study participants who contributed to this study and all the researchers, clinicians and technical and administrative staff who have made this work possible. This project received technical and data management support from OVCARE's core units, including the Cheryl Brown Ovarian Cancer Outcomes Unit and the Genetic Pathology Evaluation Centre, and statistical analysis support from the Biostatistics Core of the Norris Comprehensive Cancer Center. The AOV study recognizes the valuable contributions from Mie Konno, Shuhong Liu, Michelle Darago, Faye Chambers and the staff at the Tom Baker Cancer Centre Translational Laboratories. We thank Olivier Tredan and Pierre Heudel as investigators on the TRIO14 study and Sandrine Berge-Montamat as assistant for clinical research. The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org. We thank all of the women who participated in these research programs. This work was funded by the National Institutes of Health/National Cancer Institute (NCI) Grants to SJR [grant number R01CA172404] and J.A. Doherty and MAR [grant number R01CA168758], the Canadian Institutes for Health Research (Proof-of-Principle I program, no grant number applicable) and the United States Department of Defense Ovarian Cancer Research Program [grant number OC110433]. J. Millstein and SJR received support from National Institutes of Health/National Cancer Institute [grant number P30CA014089] and J. Millstein received support from NIH/National Cancer Institute award number P01CA196569. MSA receives funding from the Janet D. Cottrelle Foundation Scholar's program managed by the BC Cancer Foundation (no grant number applicable). JG was partially supported by the National Institutes of Health/National Cancer Institute [grant number P30CA034196]. CW was a Career Enhancement Awardee of the Mayo Clinic SPORE in Ovarian Cancer [grant number P50 CA136393]. MJH received funding from Cancer Australia (1067110), DGH receives support from the Dr Chew Wei Memorial Professorship in Gynecologic Oncology, (no grant number applicable) the Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology, no grant number applicable), and the Janet D. Cottrelle Foundation (no grant number applicable). MW receives funding from the European Union's Horizon 2020 European Research Council Programme [grant number H2020 BRCA-ERC] under Grant Agreement No. 742432, as well as from the charity The Eve Appeal (https://eveappeal.org.uk/, no grant number applicable) and support from the National Institute for Health Research (NIHR, no grant number applicable) and the University College London Hospitals (UCLH) Biomedical Research Centre (no grant number applicable). GEK is supported by the Miriam and Sheldon Adelson Medical Research Foundation (no grant number applicable). BYK is funded by the American Cancer Society Early Detection Professorship [grant number SIOP-06-258-01-COUN] and the National Center for Advancing Translational Sciences (NCATS) [grant number UL1TR000124]. HRH is supported by the National Institutes of Health/National Cancer Institute [grant number K22 CA193860]. OVCARE (including the VAN study) receives core funding through the BC Cancer Foundation (no grant number applicable) and The VGH+UBC Hospital Foundation (authors AT, BG, DGH and MSA, no grant number applicable). The AOV study is supported by the Canadian Institutes of Health Research [grant number MOP-86727]. The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling [grant numbers ID 310670, ID 628903] and the Cancer Institute NSW [grant numbers ID 12/RIG/1-17, 15/RIG/1-16]. The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command [grant number DAMD17-01-1-0729], The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia [grant numbers NHMRC, ID199600, ID400413, ID400281]. BriTROC-1 was funded by Ovarian Cancer Action (to IAM and JDB) [grant number 006] and supported by Cancer Research UK [grant numbers A15973, A15601, A18072, A17197, A19274, A19694] and the National Institute for Health Research Cambridge and Imperial Biomedical Research Centres (no grant number applicable). SEARCH was supported by Cancer Research UK [grant number A16561]. The University of Cambridge receives salary support for PDPP from the NHS Clinical Academic Reserve (no grant number applicable). Samples from the Mayo Clinic were collected and provided with support of the National Institutes of Health/National Cancer Institute (NCI) P50 CA136393 (ELG, GLK, SHK, MES). S. Orsulic was funded by the Department of Defense Award W81XWH-17-1-0144. MRC Clinical Trials Unit at UCL receives funding from The Eve Appeal (The Oak Foundation) with investigators supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and MRC core funding (MR_UU_12023). BYK served on Invitae Corporation's Advisory Board from 2017 to 2018. IAM has acted on the Advisory Boards for AstraZeneca, Clovis Oncology, Tesaro, Carrick Therapeutics and Takeda. His institution receives funding from AstraZeneca. RG is on the Advisory Boards for AstraZeneca, Tesaro, Clovis and Immunogen and does consultancy work for SOTIO. She has received support to attend conferences from AstraZeneca, Roche and Tesaro. Her institution has received research funding from Boehringer Ingelheim and Lilly/Ignyta and she is the national co-ordinating investigator for the UK for trials sponsored by AstraZeneca and Tesaro and site principal investigator for trials sponsored by AstraZeneca, Tesaro, Immunogen, Pfizer, Lilly and Clovis. PAF has received grants from Novartis, BioNtech and Cepheid as well as personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi-Sankyo, TEVA, Astra Zeneca, Merck Sharp & Dohme, Myelo Therapeutics, MacroGenics, Eisai and Puma during the conduct of the study. JDB has acted on Advisory Boards for AstraZeneca and has received support from GSK to attend conferences. His institution receives funding from AstraZeneca and Aprea. UM has shares in Abcodia Ltd. Sandra Orsulic and Beth Y. Karlan have patents on predictive gene signatures in ovarian cancer (US010253368 and EU2908913). All remaining authors have declared no conflicts of interest. Funding Information: We thank all the study participants who contributed to this study and all the researchers, clinicians and technical and administrative staff who have made this work possible. This project received technical and data management support from OVCARE's core units, including the Cheryl Brown Ovarian Cancer Outcomes Unit and the Genetic Pathology Evaluation Centre, and statistical analysis support from the Biostatistics Core of the Norris Comprehensive Cancer Center. The AOV study recognizes the valuable contributions from Mie Konno, Shuhong Liu, Michelle Darago, Faye Chambers and the staff at the Tom Baker Cancer Centre Translational Laboratories. We thank Olivier Tredan and Pierre Heudel as investigators on the TRIO14 study and Sandrine Berge-Montamat as assistant for clinical research. The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org . We thank all of the women who participated in these research programs. Publisher Copyright: © 2020 The Authors
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years.Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
AB - Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years.Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
UR - https://www.scopus.com/pages/publications/85087388806
U2 - 10.1016/j.annonc.2020.05.019
DO - 10.1016/j.annonc.2020.05.019
M3 - Article
AN - SCOPUS:85087388806
SN - 0923-7534
VL - 31
SP - 1240
EP - 1250
JO - Annals of Oncology
JF - Annals of Oncology
IS - 9
ER -