Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)
Authors: Talhouk Aline , George Joshy , Wang Chen , Budden Timothy , Tan Tuan Zea , Chiu Derek S. , Kommoss Stefan , Leong Huei San , Chen Stephanie , Intermaggio Maria P. , Gilks Blake , Nazeran Tayyebeh M. , Volchek Mila , Elatre Wafaa , Bentley Rex C. , Senz Janine , Lum Amy , Chow Veronica , Sudderuddin Hanwei , Mackenzie Robertson , Leong Samuel C.Y. , Liu Geyi , Johnson Dustin , Chen Billy , Group AOCS , Alsop Jennifer , Banerjee Susana N. , Behrens Sabine , Bodelon Clara , Brand Alison H. , Brinton Louise , Carney Michael E. , Chiew Yoke-Eng , Cushing-Haugen Kara L. , Cybulski Cezary , Ennis Darren , Fereday Sian , Fortner Renée T. , García-Donas Jesús , Gentry-Maharaj Aleksandra , Glasspool Rosalind , Goranova Teodora , Greene Casey S. , Haluska Paul , Harris Holly R. , Hendley Joy , Hernandez Brenda Y. , Herpel Esther , Jimenez-Linan Mercedes , Karpinskyj Chloe , Kaufmann Scott H. , Keeney Gary L. , Kennedy Catherine J. , Köbel Martin , Koziak Jennifer M. , Larson Melissa C. , Lester Jenny , Lewsley Liz-Anne , Lissowska Jolanta , Lubiński Jan , Luk Hugh , Macintyre Geoff , Mahner Sven , McNeish Iain A. , Menkiszak Janusz , Nevins Nikilyn , Osorio Ana , Oszurek Oleg , Palacios José , Hinsley Samantha , Pearce Celeste L. , Pike Malcolm C. , Piskorz Anna M. , Ray-Coquard Isabelle , Rhenius Valerie , Rodriguez-Antona Cristina , Sharma Raghwa , Sherman Mark E. , De Silva Dilrini , Singh Naveena , Sinn Peter , Slamon Dennis , Song Honglin , Steed Helen , Stronach Euan A. , Thompson Pamela J. , Tołoczko Aleksandra , Trabert Britton , Traficante Nadia , Tseng Chiu-Chen , Widschwendter Martin , Wilkens Lynne R. , Winham Stacey J. , Winterhoff Boris , Beeghly-Fadiel Alicia , Benitez Javier , Berchuck Andrew , Brenton James D. , Brown Robert , Chang-Claude Jenny , Chenevix-Trench Georgia , deFazio Anna , Fasching Peter A. , García María J. , Gayther Simon A. , Goodman Marc T. , Gronwald Jacek , Henderson Michelle J. , Karlan Beth Y. , Kelemen Linda E. , Menon Usha , Orsulic Sandra , Pharoah Paul D.P. , Wentzensen Nicolas , Wu Anna H. , Schildkraut Joellen M. , Rossing Mary Anne , Konecny Gottfried E. , Huntsman David G. , Huang Ruby Yun-Ju , Goode Ellen L. , Ramus Susan J. , Doherty Jennifer A. , Bowtell David D. , Anglesio Michael S. 
Published: June 2020

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 &gt;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.
See related commentary by McMullen et al., p. 5271