Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

• Type of Material: Article
• Authors: Nicola S Meagher, UNSW Sydney; Kylie L Gorringe, Peter Maccallum Cancer Centre; Matthew Wakefield, Walter and Eliza Hall Institute of Medical Research; Adelyn Bolithon, University of NSW Sydney; Chi Nam I Pang, University of NSW Sydney; Derek S Chiu, The University of British Columbia; Michael S Anglesio, The University of British Columbia; Kylie-Ann Mallitt, University of NSW Sydney; Jennifer A Doherty, Huntsman Cancer Institute; Holly R Harris, Fred Hutchinson Cancer Research Center; Joellen Schildkraut, Emory University; Andrew Berchuck, Duke University; Kara L Cushing-Haugen, Fred Hutchinson Cancer Research Center; Ksenia Chezar, University of Calgary; Angela Chou, The Kinghorn Cancer Centre; Adeline Tan, UWA Medical School; Jennifer Alsop, University of Cambridge; Ellen Barlow, Royal Hospital for Women, Sydney; Matthias W Beckmann, Universitätsklinikum Erlangen; Jessica Boros, The University of Sydney; David DL Bowtell, Peter Maccallum Cancer Centre; Alison H Brand, The University of Sydney; James D Brenton, Cancer Research UK Cambridge Institute; Ian Campbell, Peter Maccallum Cancer Centre; Dane Cheasley, Peter Maccallum Cancer Centre; Joshua Cohen, David Geffen School of Medicine at UCLA; Cezary Cybulski, Pomeranian Medical University in Szczecin; Esther Elishaev, University of Pittsburgh School of Medicine; Ramona Erber, Universitätsklinikum Erlangen; Rhonda Farrell, The University of Sydney; Anna Fischer, Universitätsklinikum und Medizinische Fakultät Tübingen; Zhuxuan Fu, University of Pittsburgh Graduate School of Public Health; Blake Gilks, University of British Columbia, Faculty of Medicine; Anthony J Gill, The Kinghorn Cancer Centre; Charlie Gourley, The University of Edinburgh; Marcel Grube, Universitätsklinikum und Medizinische Fakultät Tübingen; Paul R Harnett, The University of Sydney; Arndt Hartmann, Universitätsklinikum und Medizinische Fakultät Tübingen; Anusha Hettiaratchi, UNSW Sydney; Claus K Høgdall, Rigshospitalet; Tomasz Huzarski, Pomeranian Medical University in Szczecin; Anna Jakubowska, Pomeranian Medical University in Szczecin; Mercedes Jimenez-Linan, Addenbrooke's Hospital; Catherine J Kennedy, The University of Sydney; Byoung-Gie Kim, Samsung Medical Center, Sungkyunkwan University; Jae-Weon Kim, Seoul National University College of Medicine; Jaen-Hoon Kim, Gangnam Severance Hospital; Kayla Klett, Magee-Womens Research Institute; Jennifer M Koziak, Alberta Health Services; Tiffany Lai, David Geffen School of Medicine at UCLA; Angela Laslavic, University of Pittsburgh School of Medicine; Jenny Lester, David Geffen School of Medicine at UCLA; Yee Leung, UWA Medical School; Na Li, Peter Maccallum Cancer Centre; Winston Liauw, UNSW Sydney; Belle WX Lim, Peter Maccallum Cancer Centre; Anna Linder, Göteborgs Universitet; Jan Lubinski, Pomeranian Medical University in Szczecin; Sakshi Mahale, Peter Maccallum Cancer Centre; Constantina Mateoiu, Sahlgrenska Universitetssjukhuset; Simone McInerny, Peter Maccallum Cancer Centre; Janusz Menkiszak, Pomeranian Medical University in Szczecin; Parham Minoo, University of Calgary; Suzana Mittelstadt, Universitätsklinikum und Medizinische Fakultät Tübingen; David Morris, University of New South Wales Sydney; Sandra Orsulic, David Geffen School of Medicine at UCLA; Sang-Yoon Park, National Cancer Center, Gyeonggi; Celeste Leigh Pearce, University of Michigan School of Public Health; John V Pearson, QIMR Berghofer Medical Research Institute; Malcolm C Pike, Keck School of Medicine of USC; Carmel M Quinn, UNSW Sydney; Ganendra R Mohan, King Edward Memorial Hospital for Women; Jianyu Rao, David Geffen School of Medicine at UCLA; Marjorie J Riggan, Duke University School of Medicine; Matthias Ruebner, Universitätsklinikum Erlangen; Stuart Salfinger, St John of God Subiaco Hospital; Clare L Scott, University of Melbourne; Mitul Shah, Department of Oncology; Helen Steed, University of Alberta; Colin JR Stewart, Division of Obstetrics and Gynaecology; Deepak Subramanian, Peter Maccallum Cancer Centre; Soseul Sung, Seoul National University; Katrina Tang, Prince of Wales Hospital; Paul Timpson, The Kinghorn Cancer Centre; Robyn L Ward, The University of Sydney; Rebekka Wiedenhoefer, Universitätsklinikum und Medizinische Fakultät Tübingen; Heather Thorne, Peter Maccallum Cancer Centre; Paul A Cohen, UWA Medical School; Philip Crowe, UNSW Sydney; Peter A Fasching, Universitätsklinikum Erlangen; Jacek Gronwald, Pomeranian Medical University in Szczecin; Nicholas J Hawkins, UNSW Sydney; Estrid Høgdall, Copenhagen University Hospital – Herlev and Gentofte; David G Huntsman, The University of British Columbia; Paul A James, Peter Maccallum Cancer Centre; Beth Y Karlan, David Geffen School of Medicine at UCLA; Linda E Kelemen, Medical University of South Carolina; Stefan Kommoss, Universitätsklinikum und Medizinische Fakultät Tübingen; Gottfired E Konecny, David Geffen School of Medicine at UCLA; Francesmary Modugno, University of Pittsburgh Graduate School of Public Health; Sue K Park, Seoul National University; Annette Staebler, Tübingen University Hospital; Karin Sundfeldt, University of Gothenburg; Anna H Wu, University of Southern California; Aline Talhouk, University of British Columbia; Paul DP Pharoah, University of Cambridge; Lyndal Anderson, The University of Sydney; Anna Defazio, The University of Sydney; Martin Köbel, University of Calgary; Michael L Friedlander, University of NSW Sydney; Susan J Ramus, University of NSW Sydney
• Language: English
• Date: 2022-12-15
• Publisher: American Association for Cancer Research
• Publication Version: Final Published Version
• Copyright Statement: ©2022 The Authors; Published by the American Association for Cancer Research
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-22-1206
• Title of Journal or Parent Work: Clinical Cancer Research
• Volume: 28
• Issue: 24
• Start Page: 5383
• End Page: 5395
• Grant/Funding Information: AOCS: 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 (Multi-State Applications 191, 211, and 182), 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. DOV: NCI/NIH R01CA168758, NCI/NIH R01CA112523, and NCI/NIH R01CA087538. HSA: The Health Science Alliance (HSA) Biobank acknowledges financial support from the Translational Cancer Research Network, funded by the Cancer Institute NSW. KRA: This study was partially supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HI16C1127; 0920010). POC: POC study was supported by the program of the Minister of Science and Higher Education under the name "Regional Initiative of Excellence" in 2019–2022 project number 002/RID/2018/19 amount of financing 12,000,000 PLN. PRM: The University of Pittsburgh School of Medicine Dean's Faculty Advancement Award (F. Modugno) provided support for this research. Funding was also provided by the National Science Foundation (DGE-2217399-Modugno). The views expressed are those of the authors and do not necessarily reflect the views of the National Science Foundation. This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource, which is supported in part by National Cancer Institute award P30CA047904. 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 P.D.P Pharoah from the NHS in the East of England through the Clinical Academic Reserve. 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. VIP: The Variants in Practice study was supported by the National Health and Medical Research Council of Australia (NHMRC; APP1023698; 1092856). N.S. Meagher is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program, and the Translational Cancer Research Network. K.L. Gorringe is supported by U.S. Department of Defense (OC170121), Australian National Health and Medical Research Council, and the Peter MacCallum Cancer Foundation. S.J. Ramus is supported by National Health and Medical Research Council of Australia (NHMRC) grant APP2009840. D.D.L. Bowtell is supported by the National Health and Medical Research Council of Australia [NHMRC Fellowship (APP1117044) and Program Grant APP1092856] and the U.S. Department of Defense (DoD) Ovarian Cancer Transitional Leverage Award (W81XWH‐12‐1‐0104). M. Köbel received support through the Calgary Laboratory Services research support fund (RS19-612). A. Berchuck received support through the Ovarian Cancer Research Fund (OCRF). J.D. Brenton acknowledges funding and support from Cancer Research UK (grant numbers A22905, A15601, and A17197). M.S. Anglesio 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. D.G. Huntsman 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). A. DeFazio was funded by Cancer Institute NSW grant 15/TRC/1-01. B.-G. Kim is funded through an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. K. Sundfeldt received support from the Swedish Cancer Foundation (CAN 18–384) and the Swedish state under the agreement between the Swedish government and the county council (ALFGBG-965552). The contents of the published material are solely the responsibility of the authors and do not reflect the views of NHMRC. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
• Keywords: Adenocarcinoma, Mucinous; Female; Neoplasm Staging; Gastrointestinal Neoplasms; Prognosis; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Humans
• Research Categories: Health Sciences, Public Health; Health Sciences, Obstetrics and Gynecology; Health Sciences, Oncology; Health Sciences, Epidemiology; Health Sciences, Medicine and Surgery

Abstract

Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primaryMOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and geneexpression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n ¼ 333), mucinous borderline ovarian tumors (MBOT, n ¼ 151), and upper GI (n ¼ 65) and lower GI tumors (n ¼ 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P ¼ 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P ¼ 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P ¼ 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.