Cell-free DNA promoter hypermethylation in plasma as a predictive marker for survival of patients with pancreatic adenocarcinoma
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Stine Dam Henriksen1,2,3,4, Poul Henning Madsen5, Anders Christian Larsen1, Martin Berg Johansen6, Inge Søkilde Pedersen5, Henrik Krarup4,5 and Ole Thorlacius-Ussing1,3,4
1Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark
2Department of General Surgery, Hospital of Vendsyssel, Hjørring, Denmark
3Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
4Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
5Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
6Unit of Clinical Biostatistics and Bioinformatics, Aalborg University Hospital, Aalborg, Denmark
Stine Dam Henriksen, email: firstname.lastname@example.org
Keywords: biomarker, epigenetics, methylation, pancreatic cancer, prognosis
Received: December 12, 2016 Accepted: September 13, 2017 Published: September 30, 2017
Introduction: Few prognostic biomarkers are available for pancreatic cancer. The aim of this study is to examine the correlation between the survival of pancreatic adenocarcinoma patients and hypermethylated genes in plasma-derived cell-free DNA.
Methods: Consecutive patients with pancreatic adenocarcinoma were prospectively included and staged according to the TNM classification. Methylation-specific PCR of 28 genes was conducted. A survival prediction model independent of cancer stage and stage-specific survival prediction models were developed by multivariable Cox regression analysis using backward stepwise selection.
Results: Ninety-five patients with pancreatic adenocarcinoma were included. Patients with more than 10 hypermethylated genes had a HR of 2.03 (95% CI; 1.15-3.57) compared to patients with fewer hypermethylated genes. Three survival prediction models were developed: Total group; (American Society of Anesthesiologists score (ASA)=3, GSTP1, SFRP2, BNC1, SFRP1, TFPI2, and WNT5A) Risk groups 2, 3 and 4 had a HR of 2.65 (95% CI; 1.24-5.66), 4.34 (95% CI; 1.98-9.51) and 21.19 (95% CI; 8.61-52.15), respectively, compared to risk group 1. Stage I-II; (ASA=3, SFRP2, and MESTv2) Risk groups 2, 3 and 4 had a HR of 4.83 (95% CI; 2.01-11.57), 9.12 (95% CI; 2.18-38.25) and 70.90 (95% CI; 12.63-397.96), respectively, compared to risk group 1. Stage IV; (BMP3, NPTX2, SFRP1, and MGMT) Risk group 2 had a HR of 5.23 (95% CI; 2.13-12.82) compared to risk group 1.
Conclusion: Prediction models based on cell-free DNA hypermethylation stratified pancreatic adenocarcinoma patients into risk groups according to survival. The models have the potential to work as prognostic biomarkers. However, further validation of the results is required to substantiate the findings.
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