Clustered protocadherins methylation alterations in cancer.

Abstract

BACKGROUND:

Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, β- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation.

RESULTS:

In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours.

CONCLUSIONS:

Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers.

• Authors: Ana Florencia Vega-Benedetti, Eleonora Loi, Loredana Moi, Sylvain Blois, Antonio Fadda, Manila Antonelli, Antonella Arcella, Manuela Badiali, Felice Giangaspero, Isabella Morra, Amedeo Columbano, Angelo Restivo, Luigi Zorcolo, Viviana Gismondi, Liliana Varesco, Sara Erika Bellomo, Silvia Giordano, Matteo Canale, Andrea Casadei-Gardini, Luca Faloppi, Marco Puzzoni, Mario Scartozzi, Pina Ziranu, Giuseppina Cabras, Pierluigi Cocco, Maria Grazia Ennas, Giannina Satta, Mariagrazia Zucca, Daniele Canzio, Patrizia Zavattari
• Journal: Clinical epigenetics (Clin Epigenetics) Vol. 11 Issue 1 Pg. 100 (07 09 2019) ISSN: 1868-7083 [Electronic] Germany
• PMID: 31288858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins

Topics

• Cadherins (genetics)
• CpG Islands
• DNA Methylation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• Multigene Family
• Neoplasms (genetics)
• Promoter Regions, Genetic
• Sequence Analysis, DNA