Longitudinal Serum Protein Analysis of Women with a High Risk of Developing Breast Cancer Reveals Large Interpatient Versus Small Intrapatient Variations: First Results from the TESTBREAST Study

Sophie C. Hagenaars, Lennard J.M. Dekker, Bob Ravesteijn, Ronald L.P. van Vlierberghe, Fred P.H.T.M. Romijn, Linda Verhoeff, Arjen J. Witkamp, Karin E. Schenk, Kristien B.I.M. Keymeulen, Marian B.E. Menke-Pluijmers, Anneriet E. Dassen, Birgitta A. Kortmann, Jakob de Vries, Emiel J.T. Rutgers, Yuri E.M. van der Burgt, Elma Meershoek-Klein Kranenbarg, Christa M. Cobbaert, Theo M. Luider, Wilma E. Mesker*, Rob A.E.M. Tollenaar

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection.

Original languageEnglish
Article number12399
JournalInternational Journal of Molecular Sciences
Volume23
Issue number20
DOIs
Publication statusPublished - 17 Oct 2022

Bibliographical note

Funding Information:
The TESTBREAST study was supported with research grants from the Bollenstreekfonds Lisse, Pink Ribbon (2011.VW06.C725 or Dutch Cancer Society (KWF) number UL 2016–8172), A Sisters Hope, Zabawas and Nuts-Ohra.

Publisher Copyright: © 2022 by the authors.

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