title: Tumor LINE-1 Methylation Level in Association with Survival of Patients with Stage II Colon Cancer.
abstract: Genome-wide DNA hypomethylation is associated with a worse prognosis in early-stage colorectal cancer. To measure genome-wide DNA methylation levels, long interspersed nucleotide element (LINE-1) repeats are used as a surrogate marker. Cohort studies on the clinical impact of genome-wide DNA methylation level in patients with only early-stage colon cancer, are currently lacking. This study aimed to investigate the prognostic value of LINE-1 methylation in a stage II colon cancer cohort (n= 164). Manual needle microdissection of tumor areas was performed on formalin-fixed paraffin-embedded tumor tissue sections followed by DNA extraction. Bisulfite converted DNA was used to assess tumor LINE-1 methylation level by qPCR. Patients with LINE-1 hypomethylated tumors had a significantly worse overall survival compared to patients with a higher level of LINE-1 tumor DNA methylation (HR 1.68, 95% CI 1.03-2.75;p= 0.04). This effect was more prominent in patients aged over 65 years (HR 2.00, 95% CI 1.13-3.52;p= 0.02), although the test for age interaction was not significant. No significant effect on recurrence-free survival was observed. Based on these results, tumor LINE-1 hypomethylation is associated with a worse overall survival in stage II colon cancer. Whether the origin of this causation is cancer-specific or age-related can be debated.
authors.affiliation: Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. m.swets@lumc.nl.|Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. m.swets@lumc.nl.
authors.forename: Marloes
authors.initials: M
authors.lastname: Swets
authors.affiliation: Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. anniek.z@hotmail.com.
authors.forename: Anniek
authors.initials: A
authors.lastname: Zaalberg
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. a.boot@lumc.nl.
authors.forename: Arnoud
authors.initials: A
authors.lastname: Boot
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. t.van_wezel@lumc.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.affiliation: Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. m.a.frouws@lumc.nl.
authors.forename: Martine A
authors.initials: MA
authors.lastname: Frouws
authors.affiliation: Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. e.bastiaannet@lumc.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: Bastiaannet
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. a.j.gelderblom@lumc.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. c.j.h.van_de_velde@lumc.nl.
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.affiliation: Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. p.j.k.kuppen@lumc.nl.
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor
keywords: LINE-1; biomarker; methylation; stage II colon cancer