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    Development and validation of the gene expression predictor of high-grade serous ovarian carcinoma molecular subTYPE (PrOTYPE)

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    Authors
    Talhouk, A.
    George, J.
    Wang, C.
    Budden, Timothy
    Tan, T. Z.
    Chiu, D. S.
    Kommoss, S.
    Leong, H. S.
    Chen, S.
    Intermaggio, M. P.
    Gilks, B.
    Nazeran, T. M.
    Volchek, M.
    Elatre, W.
    Bentley, R. C.
    Senz, J.
    Lum, A.
    Chow, V.
    Sudderuddin, H.
    Mackenzie, R.
    Leong, S. C. Y.
    Liu, G. Y.
    Johnson, D.
    Chen, B.
    Alsop, J.
    Banerjee, S. N.
    Behrens, S.
    Bodelon, C.
    Brand, A. H.
    Brinton, L.
    Carney, M. E.
    Chiew, Y. E.
    Cushing-Haugen, K. L.
    Cybulski, C.
    Ennis, D.
    Fereday, S.
    Fortner, R. T.
    Garcia-Donas, J.
    Gentry-Maharaj, A.
    Glasspool, R.
    Goranova, T.
    Greene, C. S.
    Haluska, P.
    Harris, H. R.
    Hendley, J.
    Hernandez, B. Y.
    Herpel, E.
    Jimenez-Linan, M.
    Karpinskyj, C.
    Kaufmann, S. H.
    Keeney, G. L.
    Kennedy, C. J.
    Kobel, M.
    Koziak, J. M.
    Larson, M. C.
    Lester, J.
    Lewsley, L. A.
    Lissowska, J.
    Lubinski, J.
    Luk, H.
    Macintyre, G.
    Mahner, S.
    McNeish, I. A.
    Menkiszak, J.
    Nevins, N.
    Osorio, A.
    Oszurek, O.
    Palacios, J.
    Hinsley, S.
    Pearce, C. L.
    Pike, M. C.
    Piskorz, A. M.
    Ray-Coquard, I.
    Rhenius, V.
    Rodriguez-Antona, C.
    Sharma, R.
    Sherman, M. E.
    De Silva, D.
    Singh, N.
    Sinn, P.
    Slamon, D.
    Song, H. L.
    Steed, H.
    Stronach, E. A.
    Thompson, P. J.
    Toloczko, A.
    Trabert, B.
    Traficante, N.
    Tseng, C. C.
    Widschwendter, M.
    Wilkens, L. R.
    Winham, S. J.
    Winterhoff, B.
    Beeghly-Fadiel, A.
    Benitez, J.
    Berchuck, A.
    Brenton, J. D.
    Brown, R.
    Chang-Claude, J.
    Chenevix-Trench, G.
    DeFazio, A.
    Fasching, P. A.
    Garcia, M. J.
    Gayther, S. A.
    Goodman, M. T.
    Gronwald, J.
    Henderson, M. J.
    Karlan, B. Y.
    Kelemen, L. E.
    Menon, U.
    Orsulic, S.
    Pharoah, P. D. P.
    Wentzensen, N.
    Wu, A. H.
    Schildkraut, J. M.
    Rossing, M. A.
    Konecny, G. E.
    Huntsman, D. G.
    Huang, R. Y. J.
    Goode, E. L.
    Ramus, S. J.
    Doherty, J. A.
    Bowtell, D. D.
    Anglesio, M. S.
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    Affiliation
    British Columbia's Gynecological Cancer Research Program (OVCARE), BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, British Columbia, Canada.
    Issue Date
    2020
    
    Metadata
    Show full item record
    Abstract
    Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.
    Citation
    Talhouk A, George J, Wang C, Budden T, Tan TZ, Chiu DS, et al. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE). Clin Cancer Res. 2020;26(20):5411-23.
    Journal
    Clinical Cancer Research
    URI
    http://hdl.handle.net/10541/623556
    DOI
    10.1158/1078-0432.Ccr-20-0103
    PubMed ID
    32554541
    Additional Links
    https://dx.doi.org/10.1158/1078-0432.Ccr-20-0103
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.Ccr-20-0103
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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