Dataset Information

Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas.

ABSTRACT: Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin- and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.

SUBMITTER: Condelli V

PROVIDER: S-EPMC7796477 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas.

Condelli Valentina V Calice Giovanni G Cassano Alessandra A Basso Michele M Rodriquenz Maria Grazia MG Zupa Angela A Maddalena Francesca F Crispo Fabiana F Pietrafesa Michele M Aieta Michele M Sgambato Alessandro A Tortora Giampaolo G Zoppoli Pietro P Landriscina Matteo M

Cancers 20210105 1

Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus re ...[more]

PMID: 33466447

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Project description:Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based upon their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simean virus 40 T/t-antigens that is associated with the biologic behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb or BRCA1 expression, but not in tumors initiated through the overexpression of myc, ras, her2/neu, or Polyoma middle T oncogenes. Importantly, human breast, lung and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Since this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Since the these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in pre-clinical testing of therapies focused on these biologically important targets. Keywords: SuperSeries Gene expression profiles from the SV40 T/t-antigen mouse models were compared with respect to specimen type (normal vs. tumor tissue), location of tumor (mammary, lung, prostate, seminal vesicle), and background strain of mice (FVB vs. C57BL/6). A three-way ANOVA model with one interaction effect (type X location) was fitted. Cancer genes that differ among all four tumor locations were identified, as those that had a significant interaction effect at the 0.001 level and showed at least a 2-fold change between the maximal and minimal mean tumor/normal ratio over the different locations (2638 cDNA probes). Based on the ANOVA model, differentially expressed genes between normal and tumor specimens within each tumor location were also identified, as those genes whose expression were significant at the 0.001 level and were at least 2-fold different compared to the mean expression ratio. Overall 3004 unique array features were selected using ANOVA. Further selection was applied based upon identification of differentially expressed genes between normal and tumor tissue for the three epithelial tumors (mammary, lung and prostate). The SV40 T/t-antigen oncogene-specific signature included genes similarly differentially expressed in each epithelial tumor (153 cDNA clones). In contrast, genes were included in a tissue-specific SV40 T/t-antigen tumor signature if they were found to be differentially expressed between the tumor and normal samples exclusively for one location. Two-hundred and eighty three, 220 and 999 cDNA clones were identified as specifically dysregulated in mammary, lung and prostate tumors, respectively).

Dataset Information

Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas.

Publications

Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas.

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