title: The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers.
abstract: We have previously shown that gastrointestinal cancers display similar epigenetic aberrations. In a recent study, we identified frequently methylated genes for cholangiocarcinoma (CDO1, DCLK1, SFRP1 and ZSCAN18), where one of these genes, DCLK1, was also confirmed to be highly methylated in colorectal cancer. The aim of the present study was to determine whether these four genes, in addition to one gene found to be methylated in colon cancer cell lines (ZNF331), are commonly methylated across gastrointestinal malignancies, as well as explore their role as potential biomarkers. Quantitative methylation specific PCR (qMSP) of colorectal cancer (n=164) and normal colorectal mucosa (n=106) samples showed that all genes were frequently methylated in colorectal cancer (71-92%) with little or no methylation in normal mucosa (0-3%). Methylation of minimum two of these five genes identified 95% of the tumors with a specificity of 98%, and an area under the receiver operating characteristics curve (AUC) of 0.98. For gastric (n=25) and pancreatic (n=20) cancer, the same panel detected 92% and 90% of the tumors, respectively. Seventy-four cancer cell lines were further analyzed by qMSP and real time RT-PCR. In addition to the previously reported DCLK1, a high negative correlation between promoter DNA methylation and gene expression was observed for CDO1, ZNF331 and ZSCAN18. In conclusion, the high methylation frequency of these genes in colorectal- as well as in gastric-, pancreatic- and bile duct cancer confirmed an epigenetic similarity between gastrointestinal cancer types, and simultaneously demonstrated their potential as biomarkers, particularly for colorectal cancer detection.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital- Norwegian Radium Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway.
authors.forename: Hege Marie
authors.initials: HM
authors.lastname: Vedeld
authors.forename: Kim
authors.initials: K
authors.lastname: Andresen
authors.forename: Ina Andrassy
authors.initials: IA
authors.lastname: Eilertsen
authors.forename: Arild
authors.initials: A
authors.lastname: Nesbakken
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Ivar P
authors.initials: IP
authors.lastname: Gladhaug
authors.forename: Espen
authors.initials: E
authors.lastname: Thiis-Evensen
authors.forename: Torleiv O
authors.initials: TO
authors.lastname: Rognum
authors.forename: Kirsten Muri
authors.initials: KM
authors.lastname: Boberg
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D050558:Cysteine Dioxygenase / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012372:ROC Curve; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C403666:ZNF331 protein, human; C579733:ZSCAN18 protein, human; C579734:CDO1 protein, human; D050558:Cysteine Dioxygenase
keywords: CDO1; DCLK1; DNA methylation; SFRP1; ZNF331; ZSCAN18; biomarker; cancer