title: Network-based analysis identifies epigenetic biomarkers of esophageal squamous cell carcinoma progression.
abstract: BACKGROUND
  A rapid progression of esophageal squamous cell carcinoma (ESCC) causes a high mortality rate because of the propensity for metastasis driven by genetic and epigenetic alterations. The identification of prognostic biomarkers would help prevent or control metastatic progression. Expression analyses have been used to find such markers, but do not always validate in separate cohorts. Epigenetic marks, such as DNA methylation, are a potential source of more reliable and stable biomarkers. Importantly, the integration of both expression and epigenetic alterations is more likely to identify relevant biomarkers.
  
  
  RESULTS
  We present a new analysis framework, using ESCC progression-associated gene regulatory network (GRN escc), to identify differentially methylated CpG sites prognostic of ESCC progression. From the CpG loci differentially methylated in 50 tumor-normal pairs, we selected 44 CpG loci most highly associated with survival and located in the promoters of genes more likely to belong to GRN escc. Using an independent ESCC cohort, we confirmed that 8/10 of CpG loci in the promoter of GRN escc genes significantly correlated with patient survival. In contrast, 0/10 CpG loci in the promoter genes outside the GRN escc were correlated with patient survival. We further characterized the GRN escc network topology and observed that the genes with methylated CpG loci associated with survival deviated from the center of mass and were less likely to be hubs in the GRN escc. We postulate that our analysis framework improves the identification of bona fide prognostic biomarkers from DNA methylation studies, especially with partial genome coverage.
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Chun-Pei
authors.initials: CP
authors.lastname: Cheng
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: I-Ying
authors.initials: IY
authors.lastname: Kuo
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Ph
authors.forename: Hakan
authors.initials: H
authors.lastname: Alakus
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Ph
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Olivier
authors.initials: O
authors.lastname: Harismendy
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Tseng
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality; D000077277:Esophageal Squamous Cell Carcinoma; D053263:Gene Regulatory Networks; D006801:Humans; D011401:Promoter Regions, Genetic
chemical_list: D014408:Biomarkers, Tumor