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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 137-147 |
| Number of pages | 11 |
| Journal | British journal of cancer |
| Volume | 128 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 26 2023 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
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In: British journal of cancer, Vol. 128, No. 1, 26.01.2023, p. 137-147.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma
T2 - an Ovarian Tumor Tissue Analysis Consortium Study
AU - AOCS Group
AU - Weir, Ashley
AU - Kang, Eun Young
AU - Meagher, Nicola S.
AU - Nelson, Gregg S.
AU - Ghatage, Prafull
AU - Lee, Cheng Han
AU - Riggan, Marjorie J.
AU - Gentry-Maharaj, Aleksandra
AU - Ryan, Andy
AU - Singh, Naveena
AU - Widschwendter, Martin
AU - Alsop, Jennifer
AU - Anglesio, Michael S.
AU - Beckmann, Matthias W.
AU - Berger, Jessica
AU - Bisinotto, Christiani
AU - Boros, Jessica
AU - Brand, Alison H.
AU - Brenton, James D.
AU - Brooks-Wilson, Angela
AU - Carney, Michael E.
AU - Cunningham, Julie M.
AU - Cushing-Haugen, Kara L.
AU - Cybulski, Cezary
AU - Elishaev, Esther
AU - Erber, Ramona
AU - Fereday, Sian
AU - Fischer, Anna
AU - Paz-Ares, Luis
AU - Gayarre, Javier
AU - Gilks, Blake C.
AU - Grube, Marcel
AU - Harnett, Paul R.
AU - Harris, Holly R.
AU - Hartmann, Arndt
AU - Hein, Alexander
AU - Hendley, Joy
AU - Hernandez, Brenda Y.
AU - Heublein, Sabine
AU - Huang, Yajue
AU - Huzarski, Tomasz
AU - Jakubowska, Anna
AU - Jimenez-Linan, Mercedes
AU - Kennedy, Catherine J.
AU - Kommoss, Felix K.F.
AU - Koziak, Jennifer M.
AU - Kraemer, Bernhard
AU - Le, Nhu D.
AU - Winham, Stacey J.
AU - Goode, Ellen L.
N1 - Funding Information: This study was funded by NCI/NIH R01CA172404 to SJR. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. AOC: The Australian Ovarian Cancer Study was supported by the U.S. Army Medical Research and Materiel Command under DAMD17‐01‐1‐0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; ID199600; ID400413 and ID400281); AOV: Canadian Institutes of Health Research (MOP‐86727).; BAV: ELAN Funds of the University of Erlangen‐Nuremberg; BRZ: Brazilian National Council for Scientific and Technological Development, grant No. 478416/2009-1; CAL: Cancer Research Society (19319) and CLS Internal Research support RS14‐5008; CNI: CNI funded by Instituto de Salud Carlos Tercero (AES grant PI19/01730) and Fondo Europeo de Desarrollo Regional, FEDER. Instituto de Salud Carlos III (PI 12/01319); Ministerio de Economía y Competitividad (SAF2012); DOV: NCI/NIH R01CA168758, NCI/NIH R01CA112523 and NCI/NIH R01CA087538; HAW: US National Institutes of Health (R01‐CA58598, N01‐CN‐55424 and N01‐PC‐67001); HOP: Department of Defense (DAMD17‐02‐1‐0669) and NCI (K07‐CA080668, R01‐CA95023, MO1‐RR000056). This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. LAX: American Cancer Society Early Detection Professorship (SIOP‐06‐258‐01‐COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; MAY: National Institutes of Health (R01‐CA122443, R01-CA243483, P30‐CA15083, P50‐CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; NCT: Parts of the study at the NCT were funded by “Heuer Stiftung für medizinische Forschung”; POC: Pomeranian Medical University; SEA: Cancer Research UK C490/A16561, the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Cambridge Cancer Centre. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. TVA: This work was supported by Canadian Institutes of Health Research grant (MOP‐86727) and by NIH/NCI 1 R01CA160669‐01A1; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) with contribution to author’s salary through MRC core funding MC_UU_00004/01 and the National Institute for Health Research University College London Hospitals Biomedical Research Centre; VAN: BC’s Gynecological Cancer Research Team (OVCARE) receives core funding from The BC Cancer Foundation and the VGH and UBC Hospital Foundation; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 and ID 628903. Cancer Institute NSW Grants 12/RIG/1‐17 and 15/RIG/1‐16. The Westmead GynBiobank acknowledges financial support from the Sydney West Translational Cancer Research Centre, funded by the Cancer Institute NSW. NSM is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program, and the Translational Cancer Research Network, a translational cancer research centre programme funded by the Cancer Institute NSW. DB is supported by the National Health and Medical Research Council of Australia (NHMRC Fellowship (APP1117044) and Program Grant APP1092856) and the United States Department of Defence (DoD) Ovarian Cancer Transitional Leverage Award (W81XWH‐12‐1‐0104); FJCdR is funded by the Brazilian National Council for Scientific and Technological Development – CNPq (427983/2016-9, 303210/2018-4). MK received support through the Calgary Laboratory Services research support fund (RS19-612). AB received support through the Ovarian Cancer Research Fund (OCRF). BYK is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), grant UL1TR000124. SH received grants from University of Heidelberg Medical Faculty, Novartis Oncology, Stiftung für Krebs- und Scharlachforschung Mannheim, and Deutsche Forschungsgemeinschaft. JDB acknowledges funding and support from Cancer Research UK (grant numbers A22905, A15601 and A17197). UKO: MW is funded by the European Union’s Horizon 2020 European Research Council Program, H2020 BRCA-ERC under Grant Agreement No. 742432. AT is funded through a Michael Smith Foundation for Health Research Scholar Award. MA is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars programme managed by the BC Cancer Foundation. DGH receives support from the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology and the Canada Research Chairs programme (Research Chair in Molecular and Genomic Pathology). Funding for ADF is funded by Cancer Institute NSW grant 15/TRC/1-01. RE was supported by the Interdisciplinary Center for Clinical Research (IZKF; Clinician Scientist Program) of the Medical Faculty FAU Erlangen-Nürnberg. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. Open Access funding enabled and organized by CAUL and its Member Institutions. 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. We thank Shuhong Liu and Young Ou for performing immunohistochemistry (Anatomical Pathology Research Laboratory, Department of Pathology and Laboratory Medicine, University of Calgary). The AOCS gratefully acknowledges additional support from S. Boldeman, the Agar family, Ovarian Cancer Action (UK), 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 http://www.aocstudy.org . We thank Mie Konno, Michelle Darago, Faye Chambers, SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy, I. Jacobs, S. Gayther, E. Wozniak, J. Ford, and N. Balogun. We thank the Genetic Pathology Evaluation Centre (GPEC) for technical support in construction of tissue micro-arrays; and the OVCARE clinical informatics core, Gynecological tissue bank (GTB), and Cheryl Brown Gynecologic Cancer Outcomes Unit for facilitating recruitment of patients, banking biospecimens, and maintaining clinical data. We thank the Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network‐Oncology group. We thank all patients who participated in and donated tissue samples to this study. We acknowledge funding and support from Cancer Research UK and the Cancer Research UK Cambridge Centre (A22905, A29580, A25117). 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. We thank Shuhong Liu and Young Ou for performing immunohistochemistry (Anatomical Pathology Research Laboratory, Department of Pathology and Laboratory Medicine, University of Calgary). The AOCS gratefully acknowledges additional support from S. Boldeman, the Agar family, Ovarian Cancer Action (UK), 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 http://www.aocstudy.org. We thank Mie Konno, Michelle Darago, Faye Chambers, SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy, I. Jacobs, S. Gayther, E. Wozniak, J. Ford, and N. Balogun. We thank the Genetic Pathology Evaluation Centre (GPEC) for technical support in construction of tissue micro-arrays; and the OVCARE clinical informatics core, Gynecological tissue bank (GTB), and Cheryl Brown Gynecologic Cancer Outcomes Unit for facilitating recruitment of patients, banking biospecimens, and maintaining clinical data. We thank the Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network‐Oncology group. We thank all patients who participated in and donated tissue samples to this study. We acknowledge funding and support from Cancer Research UK and the Cancer Research UK Cambridge Centre (A22905, A29580, A25117). Publisher Copyright: © 2022, The Author(s).
PY - 2023/1/26
Y1 - 2023/1/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141178309&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85141178309&partnerID=8YFLogxK
U2 - 10.1038/s41416-022-02014-y
DO - 10.1038/s41416-022-02014-y
M3 - Article
C2 - 36323878
AN - SCOPUS:85141178309
SN - 0007-0920
VL - 128
SP - 137
EP - 147
JO - British journal of cancer
JF - British journal of cancer
IS - 1
ER -