SNiPER: a novel hypermethylation biomarker panel for liquid biopsy based early breast cancer detection
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Jolein Mijnes1, Janina Tiedemann1, Julian Eschenbruch1, Janina Gasthaus1, Sarah Bringezu1, Dirk Bauerschlag3, Nicolai Maass3, Norbert Arnold3,6, Jörg Weimer3, Tobias Anzeneder4, Peter A. Fasching5, Matthias Rübner5, Benjamin Bruno7, Uwe Heindrichs7, Jennifer Freres7, Hanna Schulz1, Ralf-Dieter Hilgers8, Nadina Ortiz-Brüchle1, Sonja von Serenyi1, Ruth Knüchel1, Vera Kloten1,9,* and Edgar Dahl1,2,*
1 Molecular Oncology Group, Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
2 RWTH centralized Biomaterial Bank (RWTH cBMB) at the Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
3 Department of Gynecology and Obstetrics, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany
4 Patients' Tumor Bank of Hope (PATH-Biobank) Foundation, München, Germany
5 Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
6 Institute of Clinical Molecular Biology, University Medical Centre Schleswig-Holstein, Campus Kiel, Christian-Albrechts-University, Kiel, Germany
7 Department of Gynecology and Obstetrics Luisenhospital, Aachen, Germany
8 Institute of Medical Statistics, University Hospital RWTH Aachen, Aachen, Germany
9 Current address: Bayer AG, Pharmaceuticals Division, Biomarker Research, Wuppertal, Germany
* Share equal senior authorship
Keywords: liquid biopsy; breast cancer; early detection; hypermethylation; discriminative CpG dinucleotides
Received: May 13, 2019 Accepted: October 19, 2019 Published: November 05, 2019
Mammography is the gold standard for early breast cancer detection, but shows important limitations. Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography.
Potential biomarkers were identified from The Cancer Genome Atlas (TCGA), using HumanMethylation450-BeadChip data. Promoter methylation status was evaluated quantitatively by pyrosequencing in a serum test cohort (n = 103), a serum validation cohort (n = 368) and a plasma cohort (n = 125).
SPAG6, NKX2-6 and PER1 were identified as novel biomarker candidates. ITIH5 was included on basis of our previous work. In the serum test cohort, a panel of SPAG6 and ITIH5 showed 63% sensitivity for DCIS and 51% sensitivity for early invasive tumor (pT1, pN0) detection at 80% specificity. The serum validation cohort revealed 50% sensitivity for DCIS detection on basis of NKX2-6 and ITIH5. Furthermore, an inverse correlation between methylation frequency and cfDNA concentration was uncovered. Therefore, markers were tested in a plasma cohort, achieving a 64% sensitivity for breast cancer detection using SPAG6, PER1 and ITIH5.
Although liquid biopsy remains challenging, a combination of SPAG6, NKX2-6, ITIH5 and PER1 (SNiPER) provides a promising tool for blood-based breast cancer detection.
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