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      Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort

      research-article
      1 , , 2 , 1 , 1 , 1 , 3 , 4 , 4 , 4 , 5 , 5 ,   6 , 7 , 8 , 9 , 7 , 8 , 9 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 12 , 13 , 12 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 20 , 21 ,   22 , 23 , 24 , 25 , 22 , 22 , 26 , 27 , 28 , 29 , 30 , 31 , 29 , 32 , 33 , 34 , 35 , 35 , 36 , 37 , 38 , 39 , 40 , 40 , 40 , 41 , 41 , 2 , 3 , 1 , 2 , 3
      Journal of Ovarian Research
      BioMed Central
      Ovarian cancer, Early detection markers, CA125, CA15.3, HE4

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          Abstract

          Background

          Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening.

          Methods

          We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls ( n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study ( n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression.

          Results

          CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women ( p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (p trend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking ( p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers ( p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination.

          Conclusions

          This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13048-017-0315-6) contains supplementary material, which is available to authorized users.

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          Most cited references37

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          Comprehensive analysis of HE4 expression in normal and malignant human tissues.

          The HE4 (WFDC2) gene encodes a WAP-type four disulphide core domain-containing protein with a presumptive role in natural immunity. Multiple studies have consistently identified upregulation of HE4 gene expression in carcinomas of the ovary; however, the expression in normal and malignant adult tissues has not been examined in detail. Here, we examined the expression of the HE4 gene and protein in a large series of normal and malignant adult tissues by oligonucleotide microarray and tissue microarray, respectively. HE4 gene expression was highest in normal human trachea and salivary gland, and to a lesser extent, lung, prostate, pituitary gland, thyroid, and kidney. In a series of 175 human adult tumors, gene expression was highest in ovarian serous carcinomas. However, adenocarcinomas of the lung, and occasional breast, transitional cell and pancreatic carcinomas had moderate or high levels of HE4 expression. Using tissue microarrays and full tissue sections of normal and 448 neoplastic tissues, HE4 immunoreactivity was found in normal glandular epithelium of the female genital tract and breast, the epididymis and vas deferens, respiratory epithelium, distal renal tubules, colonic mucosa, and salivary glands, consistent with HE4 gene expression. In addition to consistent positivity in ovarian carcinoma, some pulmonary, endometrial, and breast adenocarcinomas, mesotheliomas, and less often, gastrointestinal, renal and transitional cell carcinomas were also positive. Knowledge of the expression patterns of HE4 in our survey is useful for application in histopathologic diagnosis, and should be taken into consideration in future studies that examine the role of HE4 as a serological tumor biomarker or as a target for gene-based therapy.
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            Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review.

            Human epididymis protein 4 (HE4) measurements in serum have been proposed for improving the specificity of laboratory identification of ovarian cancer (OC).
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              A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort.

              About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study.
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                Author and article information

                Contributors
                +49 6221 42 2241 , r.fortner@dkfz.de
                AVITONIS@partners.org
                Helena.Schock@gmx.de
                a.huesing@dkfz.de
                t.johnson@dkfz.de
                rfichorova@rics.bwh.harvard.edu
                titilayo@bu.edu
                HYAMAMOTO@partners.org
                annet@cancer.dk
                louhan@cancer.dk
                ko@ph.au.dk
                marie-christine.boutron@gustaveroussy.fr
                Marina.KVASKOFF@gustaveroussy.fr
                gianluca.severi@hugef-torino.org
                boeing@dife.de
                atrichopoulou@hhf-greece.gr
                vben@nut.uoa.gr
                carlo.lavecchia@unimi.it
                d.palli@ispo.toscana.it
                sabina.sieri@istitutotumori.mi.it
                rosario.tumino@asp.rg.it
                giuseppe.matullo@unito.it
                amattiel@unina.it
                N.C.Onland@umcutrecht.nl
                P.H.M.Peeters@umcutrecht.nl
                Elisabete.Weiderpass.Vainio@ki.se
                inger.gram@uit.no
                mie.jareid@uit.no
                JOSERAMON.QUIROSGARCIA@asturias.org
                eduell@iconcologia.net
                mariajose.sanchez.easp@juntadeandalucia.es
                mdolores.chirlaque@carm.es
                me.ardanaz.aicua@cfnavarra.es
                epidem3-san@euskadi.eus
                bjorn.nodin@med.lu.se
                jenny.brandstedt@med.lu.se
                annika.idahl@umu.se
                kk101@medschl.cam.ac.uk
                naomi.allen@ndph.ox.ac.uk
                gunterm@iarc.fr
                johanssonm@iarc.fr
                dossusl@iarc.fr
                m.merritt@imperial.ac.uk
                e.riboli@imperial.ac.uk
                DCRAMER@partners.org
                r.kaaks@dkfz.de
                KTERRY@partners.org
                Journal
                J Ovarian Res
                J Ovarian Res
                Journal of Ovarian Research
                BioMed Central (London )
                1757-2215
                20 March 2017
                20 March 2017
                2017
                : 10
                : 20
                Affiliations
                [1 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Cancer Epidemiology, , German Cancer Research Center (DKFZ), ; Im Neuenheimer Feld 280, Heidelberg, 69120 Germany
                [2 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Ob/Gyn Epidemiology Center, , Brigham and Women’s Hospital, ; Boston, MA USA
                [3 ]ISNI 000000041936754X, GRID grid.38142.3c, Obstetrics, Gynecology and Reproductive Biology, , Harvard Medical School, ; Boston, MA USA
                [4 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Laboratory of Genital Tract Biology, , Brigham and Women’s Hospital, ; Boston, MA USA
                [5 ]ISNI 0000 0001 2175 6024, GRID grid.417390.8, , Unit of Diet, Genes and Environment, Danish Cancer Society Research Center, ; Copenhagen, Denmark
                [6 ]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Department of Public Health, Section for Epidemiology, , Aarhus University, ; Aarhus, Denmark
                [7 ]INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women’s Health team, Villejuif, F-94805 France
                [8 ]ISNI 0000 0001 2171 2558, GRID grid.5842.b, , Université Paris Sud, ; UMRS 1018, Villejuif, F-94805 France
                [9 ]ISNI 0000 0001 2284 9388, GRID grid.14925.3b, , Gustave Roussy, ; Villejuif, F-94805 France
                [10 ]ISNI 0000 0004 1784 6598, GRID grid.428948.b, , Human Genetics Foundation (HuGeF), ; Torino, Italy
                [11 ]ISNI 0000 0004 0390 0098, GRID grid.418213.d, Department of Epidemiology, , German Institute of Human Nutrition Potsdam-Rehbruecke, ; Nuthetal, Germany
                [12 ]GRID grid.424637.0, , Hellenic Health Foundation, ; Athens, Greece
                [13 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, , School of Medicine, National and Kapodistrian University of Athens, ; Athens, Greece
                [14 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Clinical Sciences and Community Health, , Università degli Studi di Milano, ; Milan, Italy
                [15 ]ISNI 0000 0004 1758 0566, GRID grid.417623.5, Cancer Risk Factors and Life-Style Epidemiology Unit, , Cancer Research and Prevention Institute – ISPO, ; Florence, Italy
                [16 ]ISNI 0000 0001 0807 2568, GRID grid.417893.0, Epidemiology and Prevention Unit, , Fondazione IRCCS Istituto Nazionale dei Tumori, ; Milan, Italy
                [17 ]Cancer Registry and Histopathology Unit, “Civic - M.P-Arezzo” Hospital, ASP, Ragusa, Italy
                [18 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, Department of Medical Sciences, , University of Torino and Human Genetics Foundation – HuGeF, ; Torino, Italy
                [19 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Dipartimeno di Medicina Clinica e Chirurgia, , Federico II University, ; Naples, Italy
                [20 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Epidemiology, Julius Center for Health Sciences and Primary Care, , University Medical Center Utrecht, ; Utrecht, Netherlands
                [21 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, , School of Public Health, Imperial College, ; London, UK
                [22 ]ISNI 0000000122595234, GRID grid.10919.30, Department of Community Medicine, Faculty of Health Sciences, , University of Tromsø, The Arctic University of Norway, ; Tromsø, Norway
                [23 ]ISNI 0000 0001 0727 140X, GRID grid.418941.1, Department of Research, Cancer Registry of Norway, , Institute of Population-Based Cancer Research, ; Oslo, Norway
                [24 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, , Karolinska Institutet, ; Stockholm, Sweden
                [25 ]ISNI 0000 0004 0409 6302, GRID grid.428673.c, , Genetic Epidemiology Group, Folkhälsan Research Center, ; Helsinki, Finland
                [26 ]Public Health Directorate, Asturias, Spain
                [27 ]ISNI 0000 0004 0427 2257, GRID grid.418284.3, Cancer Epidemiology Research Program, , Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), ; Barcelona, Spain
                [28 ]Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
                [29 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, , CIBER de Epidemiología y Salud Pública (CIBERESP), ; Madrid, Spain
                [30 ]Department of Epidemiology/Murcia Health Authority, Murcia, Spain
                [31 ]ISNI 0000 0001 2287 8496, GRID grid.10586.3a, IMIB-Arrixaca, , Murcia University, CIBERESP, ; Murcia, Spain
                [32 ]Navarra Public Health Institute, Pamplona, Spain
                [33 ]IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
                [34 ]Public Health Division and BioDonostia Research Institute and CIBERESP, Basque Regional Health Department, San Sebastian, Spain
                [35 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Clinical Sciences, , Lund University, ; Lund, Sweden
                [36 ]GRID grid.411843.b, Division of Surgery, , Skåne University Hospital, ; Lund, Sweden
                [37 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Clinical Sciences, Obstetrics and Gynecology, , Umeå University, ; Umeå, Sweden
                [38 ]ISNI 0000000121885934, GRID grid.5335.0, Cancer Epidemiology Unit, , University of Cambridge, ; Cambridge, United Kingdom
                [39 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, , University of Oxford, ; Oxford, UK
                [40 ]ISNI 0000000405980095, GRID grid.17703.32, , International Agency for Research on Cancer, ; Lyon, France
                [41 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Epidemiology and Biostatistics, , School of Public Health, Imperial College London, ; London, UK
                Article
                315
                10.1186/s13048-017-0315-6
                5360038
                28320479
                3e304059-86e7-4ca6-a72d-2e5cff93b5de
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 30 January 2017
                : 8 March 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: R01 CA 158119
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: ERC-2009-AdG 232997
                Funded by: Health Research Fund (FIS)
                Award ID: PI13/00061; PI13/01162
                Funded by: FundRef http://dx.doi.org/10.13039/501100000289, Cancer Research UK;
                Award ID: 14136; C570/A16491, C8221/A19170
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: 1000143, MR/M012190/1
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Obstetrics & Gynecology
                ovarian cancer,early detection markers,ca125,ca15.3,he4
                Obstetrics & Gynecology
                ovarian cancer, early detection markers, ca125, ca15.3, he4

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