Blood-Based Detection of Preinvasive and Early High-Grade Serous Ovarian Cancer in Women via the Microenvironment-Fitness RNA Marker "Tu-Stroma"

Full author list:

Jochen Wilhelm^1,#, Amit Kumar^2,#, Narsimha Mamidi^2,3,#, Zhaoyu Sun⁴, Jinkal Modi², Aenya Gogna⁵, Praveen Bhoopathi⁶, Keshav C. Gogna², Tytus Bernas⁶, Chelsea Salyer⁷, Amy Lu², Arunima Punjala⁴, Jaclyn Wall⁷, Vignesh Vudatha⁶, Andrew S. Poklepovic⁶, Masaki Nagane⁸, Kumari S. Shree^2,, Emad A Rakha^9,10, Miguel L Rufail¹¹, Hope Richard¹¹, Anusha Challa⁴, Sriram Sriperumbuduri⁴, Sadia Sayeed¹¹, Katherine P. Klein⁷, David Chelmow⁷, Karuppaiyah Selvendiran¹², George L. Maxwell¹³, Jamie N Bakkum-Gamez¹⁴, Shariska Petersen Harrington¹⁴, Elnaz Abbasi Farid^15,16, Nadia Traficante^17,18, David Bowtell^17,18, Christopher D. Collier¹⁹, Rebecca Z. Drexler²⁰, Christine Kramer²¹, Mary M. Mullen²¹, Alexandar Tzankov²², Kirsten D. Mertz²², Jun Watanabe²³, Shimpei Nagai²³, Tatsuyuki Chiyoda²³, Wataru Yamagami²³, Kenta Masuda²³, Elena Garre²⁴, Göran Landberg²⁴, David L Kolin²⁵, Calla O'Connor²⁶, Maria E Teves⁷, Tom Li²⁷, Dongyu Zhang⁴, Karanvir Prakash²⁸, Sarah A Ackroyd²⁵, Bodour Salhia²⁹, Paola A Gehrig³⁰, Aanya Singh⁴, Jordan Lewis³¹, Lien Hoang³¹, Janice S. Kwon³², Jasmin D. Haslbauer²², Mark P. Kühnel^33,34, T. Rinda Soong³⁵, Sarah Taylor³⁶, Carlos Zuazo³⁷, Sourat Darabi³⁷, Michael J Demeure³⁷, Marc R. Radke³⁸, Denise Connolly³⁹, Barbara S. Norquist³⁸, Jose Trevino³, Nozomi Yachida⁴⁰, Kazuaki Suda⁴⁰, Kosuke Yoshihara⁴⁰, Tu-Yung Chang⁴¹, Patrick Martin⁴², Kyoung Jae Won⁴², Tian-Li Wang^41,43, Ie-Ming Shih^41,43, Thomas Russell Pisanic⁴⁴, Tanvir K Dhaliwal⁴, Vandanaa Jayaprakash⁴, Bukola Adeshina⁴⁵, Doreen Akorwome⁴, Nolan A Wages⁴⁶, Mikhail G Dozmorov⁴⁶, Seungpyo Hong^3,47,48, Ana Blanca⁴⁹, Cesar M. Castro^50,51, Elizabeth M. Swisher³⁸, Allan Tsung⁵², Ernst Lengyel²⁶, Susan Domchek⁵³, William L. Redmond⁴, Yonglun Luo⁵⁴, Ole Mogensen⁵⁵, Bo R Rueda^25,56,57, Ronny Drapkin⁵³, Andrew K. Godwin^58,59, Ronald J Buckanovich^60,61, Kenneth P. Nephew^15,16, Rafael J Luque⁶², Antonio Lopez-Beltran^63,64,65, Robert L Coleman⁶⁶, David Sidransky⁶⁷, Maximilian Ackermann^68,69, Danny Jonigk^33,34, Steven R Grossman³⁷, Ranjit Manchanda^70,71,72, Esha Madan^2,@, Rajan Gogna^2,@

1.    Institute for Lung Health (ILH), Universities Giessen & Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany.
2.    Cell Competition in Tumour Microenvironment Laboratory, Hoag Family Cancer Institute, Newport Beach, CA, 92663,USA.
3.    Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin, Madison, WI 53705.
4.    Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States.
5.    Sage Hill School, 20402 Newport Coast Dr, Newport Coast, CA 92657, USA.
6.    Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
7.    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Virginia Commonwealth University, VCU School of Medicine, Richmond, VA, 23298-0662, USA.
8.    Department of Biochemistry, School of Veterinary Medicine, Azabu University, Kanagawa, Japan.
9.    Department of Histopathology, Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
10.    Nottingham Breast Cancer Research Centre, School of Medicine, Academic Unit for Translational Medical Sciences, University of Nottingham, Nottingham, UK.
11.    Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
12.    Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
13.    Inova Women’s Service Line and the Inova Schar Cancer Institute, Falls Church, VA, USA
14.    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mayo Clinic, MN, 55905, USA.
15.    Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA.
16.    Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
17.    Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
18.    Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3000, Australia.
19.    Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
20.    Division of Endocrinology, Metabolism and Lipid Research, John T. Milliken Department of Medicine. Washington University, St. Louis, Missouri, 63110, USA
21.    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, 63110,USA
22.    Institute of Medical Genetics and Pathology, University Hospital Basel and University of Basel, Basel, Switzerland.
23.    Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
24.    Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
25.    Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA 02114, USA
26.    Department of Obstetrics and Gynecology. University of Chicago, Chicago, IL, 60637
27.    Department of Biology, University of Florida, Gainesville, Florida, USA
28.    VCU Division of Orthopedics, Virginia Commonwealth University, VCU School of Medicine, Richmond, VA, USA
29.    Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA,90033, USA
30.    Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA 22903, USA
31.    Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
32.    Division Gynecology Oncology, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada
33.    Institute of Pathology, RWTH Aachen Medical University, D-52074 Aachen, Germany.
34.    Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hanover, Germany. 
35.    Department of Pathology, University of Pittsburgh School of Medicine, PA, 15213, USA.
36.    Department of Obstetrics and Gynecology, University of Pittsburgh School of Medicine.
37.    Department of Precision Medicine, Hoag Family Cancer Institute, Newport Beach, CA, USA
38.    Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, 98195, USA.
39.    Fox Chase Cancer Center, Biosample Repository Facility, Philadelphia, PA, USA
40.    Dept. Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 950-2181, Japan 
41.    Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 
42.    Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
43.    Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
44.    The Johns Hopkins Institute for Nanobiotechnology, Johns Hopkins School of Medicine, Baltimore, MD 21218, USA
45.    Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25705, USA.
46.    Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA.
47.    Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI, USA.
48.    Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. 
49.    Departamento de Patología, Centro Clínico Champalimaud, Lisboa, Portugal.
50.    Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA USA.
51.    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.
52.    Department of Surgery, Division of Surgical Oncology, University of Virginia, Charlottesville, VA, USA.
53.    Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
54.    Department of Biomedicine, Aarhus University, 8000 Aarhus Centrum, Denmark.
55.    Department of Clinical Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
56.    Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
57.    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 55 Fruit St, Massachusetts General Hospital, Boston, MA, 02114, USA.
58.    Department of Pathology and Laboratory Medicine; University of Kansas Medical Center; Kansas City, KS, USA.
59.    Kansas Institute for Precision Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
60.    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UPMC Hillman Cancer Center and the Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA.
61.    Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
62.    Pathological Anatomy Unit, University Hospital of Jaén, Jaén, Spain.
63.    Department of Morphological Sciences, Cordoba University Medical School, Avda. Menendez-Pidal S/N, 14004, Cordoba, Spain. 
64.    Departamento de Patología, Centro Clínico Champalimaud, Lisboa, Portugal.
65.    Department of Surgery, Cordoba University Medical School, 14071 Cordoba, Spain.
66.    Gynecologic Oncology, Texas Oncology, The Woodlands, Texas, 77380, USA. 
67.    Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 
68.    Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
69.    Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Wuppertal, Germany. 
70.    Department of Gynaecological Oncology, Barts Health NHS Trust, Royal London Hospital, Whitechapel Road, London E1 1BB, UK
71.    Department of Health Services Research, Faculty of Public Health & Policy, London School of Hygiene & Tropical Medicine, 15-17 Tavistock Place, London WC1H 9SH, UK
72.    Centre for Cancer Screening, Prevention & Early Diagnosis (CCSPED), Wolfson Institute of Population Health, Queen Mary University of London, London, UK

# - These authors contributed equally for first author position.

$ - These authors contributed equally for second author position.

@ - These authors jointly supervised this work.

Corresponding Authors:

Dr. Rajan Gogna

Director of Translational Research, Hoag Family Cancer Institute, Newport Beach, CA, 92663,USA.

Email: rajangogna@gmail.com ; rajan.gogna@hoag.org

Phone: +1 6282526501

Dr. Esha Madan

Head of Cell Competition in Tumour Microenvironment Laboratory, Hoag Family Cancer Institute, Newport Beach, CA, 92663, USA.

Email: esha.madan@hoag.org

Phone: +1 8046184211

Abstract

High-grade serous carcinoma (HGSC), the most prevalent histotype of epithelial ovarian cancer and responsible for the majority of ovarian cancer–related mortality, arises from serous tubal intraepithelial carcinoma (STIC), a non-invasive precursor typically identifiable only by histopathologic examination of excised fallopian tube tissue. We evaluated Tu-Stroma, a tumor-associated long non-coding RNA enriched in serum extracellular vesicles (EVs), as a circulating biomarker in patients with STIC and early-stage HGSC, representing the earliest histopathologically defined phases of disease. Tu-Stroma was quantified in serum EVs from 506 individuals with histologically normal adnexa, benign adnexal lesions, isolated STIC and HGSC (FIGO I–IV) using a prespecified training–validation framework with independent validation. In these retrospective multi-institutional cohorts, normalized EV Tu-Stroma Δc_T values were elevated in STIC and HGSC compared with controls and benign adnexal lesions, including among premenopausal women. In paired head-to-head ROC analyses within the same individuals, Tu-Stroma showed higher discrimination than CA125 for STIC versus controls and for STIC/HGSC versus benign adnexal masses. Tu-Stroma values showed no systematic elevation across the inflammatory, physiologic and non-ovarian malignancy comparator cohorts tested, consistent with disease-context specificity in these cohorts. In modelled risk-enriched early-diagnosis contexts, predictive values were compatible with further evaluation in intended-use populations. These findings identify Tu-Stroma as a candidate EV-RNA marker associated with pre-invasive and early HGSC biology. Prospective validation in consecutively enrolled, real-world cohorts will be required to define diagnostic performance, predictive value, clinical utility and integration with existing care pathways.