title: The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription.
abstract: All colorectal cancer cell lines except RKO displayed active β-catenin/TCF regulated transcription. This feature of RKO was noted in familial colon cancers; hence our aim was to dissect its carcinogenic mechanism. MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray of RKO versus 7 colon cancer lines (with active Wnt signaling) and 3 normal specimens revealed 611 differentially expressed genes. The majority of the tested gene loci were susceptible to LOH in primary tumors with various β-catenin localizations as a surrogate marker for β-catenin activation. The immunohistochemistry of selected genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1) confirmed that they were differentially expressed in clinical specimens. Since epigenetic mechanisms can contribute to expression changes, selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI, and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. The overall fraction of hypermethylated genes was higher in tumors with membranous β-catenin. We identified novel genes in colorectal carcinogenesis that might be useful in personalized tumor profiling. Tumors with inactive Wnt signaling are a heterogeneous group displaying interaction of chromosomal instability, Wnt signaling, and epigenetics.
authors.affiliation: Department of Medical Laboratory Sciences, College of Health Sciences and Sharjah Institute for Medical Research (SIMR), University of Sharjah, P.O. Box 27272, Sharjah, UAE; Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Wael M
authors.identifier: 0000-0002-2149-1043
authors.initials: WM
authors.lastname: Abdel-Rahman
authors.affiliation: Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Lotsari-Salomaa
authors.affiliation: Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Sippy
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Niskakoski
authors.affiliation: Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00029 HUS, Finland.
authors.forename: Sakari
authors.identifier: 0000-0001-5592-3839
authors.initials: S
authors.lastname: Knuutila
authors.affiliation: Second Department of Surgery, Helsinki University Central Hospital, Helsinki, 00029 HUS, Finland.
authors.forename: Heikki
authors.identifier: 0000-0002-5318-4507
authors.initials: H
authors.lastname: Järvinen
authors.affiliation: Department of Surgery, Jyväskylä Central Hospital, 40620 Jyväskylä, Finland; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.affiliation: Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Päivi
authors.identifier: 0000-0001-8819-2980
authors.initials: P
authors.lastname: Peltomäki