Research Papers:

HYAL2 methylation in peripheral blood as a potential marker for the detection of pancreatic cancer: a case control study

Sarah Schott, Rongxi Yang, Sarah Stöcker, Federico Canzian, Nathalia Giese, Peter Bugert, Frank Bergmann, Oliver Strobel, Thilo Hackert, Christof Sohn and Barbara Burwinkel _

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Oncotarget. 2017; 8:67614-67625. https://doi.org/10.18632/oncotarget.18757

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Sarah Schott1,2,3,*, Rongxi Yang1,2,4,*, Sarah Stöcker1,4, Federico Canzian5, Nathalia Giese6, Peter Bugert7, Frank Bergmann8, Oliver Strobel6, Thilo Hackert6, Christof Sohn2 and Barbara Burwinkel1,4

1Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, 69120 Heidelberg, Germany

2Department of Gynecology and Obstetrics, University Women’s Clinic, 69120 Heidelberg, Germany

3German Cancer Consortium (DKTK), NCT Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

4Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

5Genomic Epidemiology Group (C055), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

6Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany

7Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, German Red Cross Blood Service Baden-Württemberg – Hessen, 68167 Mannheim, Germany

8Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany

*These authors have contributed equally to this work

Correspondence to:

Barbara Burwinkel, email: [email protected]

Rongxi Yang, email: [email protected]

Keywords: HYAL2, methylation, pancreatic cancer, early detection, marker

Received: October 19, 2016    Accepted: May 23, 2017    Published: June 27, 2017


Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy which is mostly diagnosed in advanced and inoperable stages though surgery remains the only curable therapeutic approach. Early detection markers are urgently needed to improve diagnosis. Altered hyaluronoglucosaminidase 2 gene (HYAL2) DNA methylation in peripheral blood is known to be associated with malignancy at early stage but has not been evaluated in PDAC patients. This study evaluates the association between blood-based HYAL2 methylation and PDAC by a case-control study with 191 controls and 82 PDAC patients. Decreased methylation of all four investigated HYAL2 methylation sites showed highly significant association with PDAC (odds ratio (ORs) per -10% methylation ranging from 2.03 to 12.74, depending on the specific CpG site, p < 0.0001 for all). HYAL2 methylation sites were also distinguishable between stage I&II PDAC (61 subjects) and controls (ORs per-10% methylation from 3.17 - 23.04, p < 0.0001 for all). Thus, HYAL2 methylation level enabled a very good discrimination of PDAC cases from healthy controls (area under curve (AUC) = 0.92, 95% Confidence interval (C.I.): 0.88 - 0.96), and was also powerful for the detection of PDAC at stage I&II (AUC = 0.93, 95% C.I.: 0.89 - 0.98). Moreover, the blood-based HYAL2 methylation pattern was similar among PDAC patients with differential clinical characteristics, and showed no correlation with the overall survival of PDAC patients. Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and PDAC, and provides a promising blood-based marker for the detection of PDAC.

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