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

Talhouk A, George J, Wang C, Budden T, Tan TZ, Chiu DS, Kommoss S, Leong HS, Chen S, Intermaggio MP, Gilks B, Nazeran TM, Volchek M, Elatre W, Bentley RC, Senz J, Lum A, Chow V, Sudderuddin H, Mackenzie R, Leung S, Liu G, Johnson D, Chen B, Ovarian Cancer Study A, Alsop J, Banerjee S, Behrens S, Bodelon C, Brand AH, Brinton LA, Carney ME, Chiew YE, Cushing-Haugen KL, Cybulski C, Ennis D, Fereday S, Fortner RT, García-Donás J, Gentry-Maharaj A, Glasspool R, Goranova T, Greene CS, Haluska P, Harris HR, Hendley J, Hernandez BY, Herpel E, Jimenez-Linan M, Karpinskyj C, Kaufmann SH, Keeney G, Kennedy CJ, Köbel M, Koziak J, Larson MC, Lester J, Lewsley LA, Lissowska J, Lubiński J, Luk H, Macintyre G, Mahner S, McNeish IA, Menkiszak J, Nevins N, Osorio A, Oszurek O, Palacios J, Hinsley S, Pearce CL, Pike MC, Piskorz A, Ray-Coquard I, Rhenius V, Rodríguez-Antona C, Sharma R, Sherman ME, Silva D, Singh N, Sinn HP, Slamon DJ, Song H, Steed H, Stronach EA, Thompson PJ, Tołoczko-Grabarek A, Trabert B, Traficante N, Tseng CC, Widschwendter M, Wilkens LR, Winham SJ, Winterhoff BJ, Beeghly-Fadiel A, Benitez J, Berchuck A, Brenton JD, Brown R, Chang-Claude J, Chenevix-Trench G, DeFazio A, Fasching P, Garcia MJ, Gayther SA, Goodman MT, Gronwald J, Henderson MJ, Karlan BY, Kelemen LE, Menon U, Orsulic S, Pharoah PD, Wentzensen N, Wu AH, Shildkraut J, Rossing MA, Konecny GE, Huntsman DG, Huang RYJ, Goode EL, Ramus SJ, Doherty JA, Bowtell DD, Anglesio MS (2020)

Publication Type: Journal article

Publication year: 2020

Journal

DOI: 10.1158/1078-0432.CCR-20-0103

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 non-standardized 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 1650 tumors. We applied resulting models to NanoString data on 3829 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 was 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 analytical 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.

Authors with CRIS profile

Involved external institutions

Peter MacCallum Cancer Centre Australia (AU) University of California Los Angeles (UCLA) United States (USA) (US) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Mayo Clinic United States (USA) (US) University of Glasgow United Kingdom (GB) University of Sydney (USYD) Australia (AU) University of British Columbia Canada (CA) University of Cambridge United Kingdom (GB) Fred Hutchinson Cancer Research Center United States (USA) (US) Vanderbilt University United States (USA) (US) Children's Cancer Institute Australia Australia (AU) University College London (UCL) United Kingdom (GB) Memorial Sloan Kettering Cancer Center United States (USA) (US) Addenbrooke's Hospital United Kingdom (GB) Duke University Medical Center United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) University of Southern California (USC) United States (USA) (US) University of Hawaiʻi at Mānoa United States (USA) (US) National University of Singapore (NUS) Singapore (SG) Alberta Health Services (AHS) Canada (CA) Universitätsklinikum Tübingen Germany (DE) Huntsman Cancer Institute United States (USA) (US) University of New South Wales (UNSW) Australia (AU) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Royal Alexandra Hospital (RAH) Canada (CA) University of Hawaii (U.H.) United States (USA) (US) The Royal Women's Hospital Australia (AU) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) National Cancer Institute (NCI) United States (USA) (US) Beatson West of Scotland Cancer Centre (BWSCC) United Kingdom (GB) Simon Fraser University Canada (CA) University of Pennsylvania United States (USA) (US) Jackson Laboratory for Genomic Medicine United States (USA) (US) HM Hospitales Spain (ES) Royal Marsden Hospital / The Royal Marsden NHS Foundation Trust United Kingdom (GB) University of Calgary Canada (CA) University of Michigan–Ann Arbor United States (USA) (US) Ruprecht-Karls-Universität Heidelberg Germany (DE) University of Minnesota (UMN) United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Klinikum der Universität München Germany (DE) Strangeways Research Laboratory United Kingdom (GB) Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) Spain (ES) Barts Health NHS Trust United Kingdom (GB) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Keck School of Medicine of USC United States (USA) (US) University of Virginia (UVA) United States (USA) (US) National Taiwan University (NTU) Taiwan (TW) Medical University of South Carolina (MUSC) United States (USA) (US)

How to cite

APA:

Talhouk, A., George, J., Wang, C., Budden, T., Tan, T.Z., Chiu, D.S.,... Anglesio, M.S. (2020). Development and validation of the gene-expression Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE). Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-20-0103

MLA:

Talhouk, Aline, et al. "Development and validation of the gene-expression Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE)." Clinical Cancer Research (2020).

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