Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study
Authors: Weir Ashley , Kang Eun-Young , Meagher Nicola S. , Nelson Gregg S. , Ghatage Prafull , Lee Cheng-Han , Riggan Marjorie J. , Gentry-Maharaj Aleksandra , Ryan Andy , Singh Naveena , Widschwendter Martin , Alsop Jennifer , Anglesio Michael S. , Beckmann Matthias W. , Berger Jessica , Bisinotto Christiani , Boros Jessica , Brand Alison H. , Brenton James D. , Brooks-Wilson Angela , Carney Michael E. , Cunningham Julie M. , Cushing-Haugen Kara L. , Cybulski Cezary , Elishaev Esther , Erber Ramona , Fereday Sian , Fischer Anna , Paz-Ares Luis , Gayarre Javier , Gilks Blake C. , Grube Marcel , Harnett Paul R. , Harris Holly R. , Hartmann Arndt , Hein Alexander , Hendley Joy , Hernandez Brenda Y. , Heublein Sabine , Huang Yajue , Huzarski Tomasz , Jakubowska Anna , Jimenez-Linan Mercedes , Kennedy Catherine J. , Kommoss Felix K. F. , Koziak Jennifer M. , Kraemer Bernhard , Le Nhu D. , Lesnock Jaime , Lester Jenny , Lubiński Jan , Menkiszak Janusz , Ney Britta , Olawaiye Alexander , Orsulic Sandra , Osorio Ana , Robles-Díaz Luis , Ruebner Matthias , Shah Mitul , Sharma Raghwa , Shvetsov Yurii B. , Steed Helen , Talhouk Aline , Taylor Sarah E. , Traficante Nadia , Vierkant Robert A. , Wang Chen , Wilkens Lynne R. , Winham Stacey J. , Benitez Javier , Berchuck Andrew , Bowtell David D. , Candido dos Reis Francisco J. , Cook Linda S. , DeFazio Anna ,   AOCs group, Bowtell D. , DeFazio A. , Traficante N. , Fereday S. , Brand A. , Harnett P. , Sharma R. , Doherty Jennifer A. , Fasching Peter A. , García María J. , Goode Ellen L. , Goodman Marc T. , Gronwald Jacek , Huntsman David G. , Karlan Beth Y. , Kommoss Stefan , Modugno Francesmary , Schildkraut Joellen M. , Sinn Hans-Peter , Staebler Annette , Kelemen Linda E. , Ford Caroline E. , Menon Usha , Pharoah Paul D. P. , Köbel Martin , Ramus Susan J. 
Published: November 2022

Abstract
Background
Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.

Methods
Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.

Results
Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67–0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant.

Conclusion
We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.