Dataset Information

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression.

ABSTRACT: Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was to test whether methylation-based biomarkers could be detected in non-invasive matrices. Our results confirmed methylation alterations of GRIA4 and VIPR2 in CRC tissues, using MethyLight, as well as in stool samples, using a much more sensitive technique as droplet digital PCR. Furthermore, we analysed expression levels of selected genes whose promoter CGIs were hypermethylated in CRC, detecting downregulation at mRNA and protein levels in CRC tissue for GRIA4, VIPR2, SPOCK1 and SLC6A3. Most of these genes were already lowly expressed in colon normal tissues supporting the idea that cancer DNA methylation targets genes already barely expressed in the matched normal tissues. Our study suggests GRIA4 and VIPR2 as biomarkers for early CRC diagnosis using stool samples and confirms downregulation of genes hypermethylated in CRC.

SUBMITTER: Vega-Benedetti AF

PROVIDER: S-EPMC7349989 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression.

Vega-Benedetti Ana Florencia AF Loi Eleonora E Moi Loredana L Orrù Sandra S Ziranu Pina P Pretta Andrea A Lai Eleonora E Puzzoni Marco M Ciccone Letizia L Casadei-Gardini Andrea A Cabras Francesco F Fortunato Federica F Restivo Angelo A Zorcolo Luigi L Scartozzi Mario M Zavattari Patrizia P

International journal of molecular sciences 20200624 12

Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was ...[more]

PMID: 32599859

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Project description:BackgroundThe development and application of CRISPR technologies for the modification of the genome are rapidly expanding. Advances in the field describe new CRISPR components that are strategically engineered to improve the precision and reliability of CRISPR editing within the genome sequence. Genome modification using induced genome breaks that are targeted and mediated by CRISPR components leverage cellular mechanisms for repair like homology directed repair (HDR) to incorporate genomic edits with increased precision.ResultsIn this report, we describe the gain of methylation at typically hypomethylated CpG island (CGI) locations affected by the CRISPR-mediated incorporation of donor DNA using HDR mechanisms. With characterization of CpG methylation patterns using whole genome bisulfite sequencing, these CGI methylation disruptions trace the insertion of the donor DNA during the genomic edit. These insertions mediated by homology-directed recombination disrupt the generational methylation pattern stability of the edited CGI within the cells and their cellular lineage within the animal strain, persisting across generations. Our approach describes a statistically based workflow for indicating locations of modified CGIs and provides a mechanism for evaluating the directed modification of the methylome of the affected CGI at the CpG-level.ConclusionsWith advances in genome modification technology comes the need to detect the level and persistence of methylation change that modifications to the genomic sequence impose upon the collaterally edited methylome. Any modification of the methylome of somatic or germline cells could have implications for gene regulation mechanisms governed by the methylation patterns of CGI regions in the application of therapeutic edits of more sensitively regulated genomic regions. The method described here locates the directed modification of the mouse epigenome that persists over generations. While this observance would require supporting molecular observations such as direct sequence changes or gene expression changes, the observation of epigenetic modification provides an indicator that intentionally directed genomic edits can lead to collateral, unintentional epigenomic changes post modification with generational persistence.

Dataset Information

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression.

Publications

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression.

Similar Datasets

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