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EGFR and EGFR ligands in serum in healthy women; reference intervals and age dependency

Ina Mathilde Kjær ORCID logo EMAIL logo , Dorte Aalund Olsen , Anne Alnor ORCID logo , Ivan Brandslund ORCID logo , Troels Bechmann ORCID logo and Jonna Skov Madsen ORCID logo



The epidermal growth factor receptor (EGFR) system is involved in cancer pathogenesis and serves as an important target for multiple cancer treatments. EGFR and its ligands epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF), betacellulin (BTC), amphiregulin (AREG) and transforming growth factor α (TGF-α) have potential applications as prognostic or predictive serological biomarkers in cancer. The aim was to establish EGFR and EGFR ligand reference intervals in healthy women.


EGFR and EGFR ligands were measured in serum from 419 healthy women aged 26–78 years. The need for age partitioned reference intervals was evaluated using Lahti’s method. EGFR and EGF were analyzed using ELISA assays, whereas HB-EGF, BTC, AREG and TGF-α were analyzed using the highly sensitive automated single molecule array (Simoa) enabling detection below the lower reference limit for all six biomarkers.


Reference intervals for EGFR and the EGFR ligands were determined as the 2.5th and 97.5th percentiles. All six biomarkers were detectable in all serum samples. For EGFR, EGF, HB-EGF and TGF-α, reference intervals were established for women <55 years and for women >55 years, whilst common reference intervals were established for AREG and BTC including women aged 26–78 years.


Age specific reference intervals were determined for EGFR, EGF, HB-EGF, BTC, AREG and TGF-α.

Corresponding author: Ina Mathilde Kjær MD, Department of Biochemistry and Immunology, Lillebaelt Hospital, University Hospital of Southern Denmark, Beriderbakken 4, 7100 Vejle, Denmark; and Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark


Oluf Borbye Pedersen, Torben Hansen, and Cramer Christensen are acknowledged for providing the blood samples from Vejle Diabetes Biobank to the study. Assistant Jannie Møller and laboratory technicians Camilla Davidsen and Sara Egsgaard are acknowledged for their excellent contributions to this work. OPEN, Patient data Explorative Network, Odense University Hospital, Odense, Denmark are acknowledged for the collaboration on data management.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: The study was supported by grants from the Research Committee, Lillebaelt Hospital, Vejle, Denmark, the Region of Southern Denmark, and from the University of Southern Denmark.

  3. Employment or leadership: Ivan Brandslund is a member of the editorial board of Clinical Chemistry and Laboratory Medicine.

  4. Honorarium: None declared.

  5. Competing interests: No funding organization played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


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Received: 2019-04-07
Accepted: 2019-06-17
Published Online: 2019-07-16
Published in Print: 2019-11-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

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