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. 2016;2016:6089658.
doi: 10.1155/2016/6089658. Epub 2016 Mar 7.

The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription

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Free PMC article

The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription

Wael M Abdel-Rahman et al. Gastroenterol Res Pract. .
Free PMC article

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.

Figures

Figure 1
Figure 1
A representative metaphase from RKO cell line. Note that rearranged chromosomes described in Section 3 and not seen here were observed in two or more other metaphases.
Figure 2
Figure 2
Cluster analysis based on the cDNA expression profiling of all colorectal cancer cell lines and normal colon specimens. The analysis was performed on GeneSpring GX software, version 11.0.2, Agilent Technologies.
Figure 3
Figure 3
High frequency of LOH at all tested loci in 22 sporadic MSS colorectal cancers (12 with nuclear and 10 with membranous β-catenin) indicates significant role of the differentially expressed genes in carcinogenesis.
Figure 4
Figure 4
Frequency of promoter hypermethylation for all selected genes in the three categories of tumors. y-axis indicates the percentage of tumors showing hypermethylation, based on cut-off values given in Supplementary Table S4.

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