Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations.

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State: Public
Version: author
Serval ID
serval:BIB_085EA78EAF45
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations.
Journal
Human Molecular Genetics
Author(s)
Barekati Zeinab, Radpour Ramin, Kohler Corina, Zhang Bei, Toniolo Paolo, Lenner Per, Lv Qing, Zheng Hong, Zhong Xiao Yan
ISSN
1460-2083[electronic], 0964-6906[linking]
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
19
Number
15
Pages
2936-2946
Language
english
Abstract
The present study investigated promoter hypermethylation of TP53 regulatory pathways providing a potential link between epigenetic changes and mitochondrial DNA (mtDNA) alterations in breast cancer patients lacking a TP53 mutation. The possibility of using the cancer-specific alterations in serum samples as a blood-based test was also explored. Triple-matched samples (cancerous tissues, matched adjacent normal tissues and serum samples) from breast cancer patients were screened for TP53 mutations, and the promoter methylation profile of P14(ARF), MDM2, TP53 and PTEN genes was analyzed as well as mtDNA alterations, including D-loop mutations and mtDNA content. In the studied cohort, no mutation was found in TP53 (DNA-binding domain). Comparison of P14(ARF) and PTEN methylation patterns showed significant hypermethylation levels in tumor tissues (P < 0.05 and <0.01, respectively) whereas the TP53 tumor suppressor gene was not hypermethylated (P < 0.511). The proportion of PTEN methylation was significantly higher in serum than in the normal tissues and it has a significant correlation to tumor tissues (P < 0.05). mtDNA analysis revealed 36.36% somatic and 90.91% germline mutations in the D-loop region and also significant mtDNA depletion in tumor tissues (P < 0.01). In addition, the mtDNA content in matched serum was significantly lower than in the normal tissues (P < 0.05). These data can provide an insight into the management of a therapeutic approach based on the reversal of epigenetic silencing of the crucial genes involved in regulatory pathways of the tumor suppressor TP53. Additionally, release of significant aberrant methylated PTEN in matched serum samples might represent a promising biomarker for breast cancer.
Keywords
Breast Neoplasms/genetics, Breast Neoplasms/pathology, CpG Islands/genetics, DNA Methylation/genetics, DNA Mutational Analysis, DNA, Mitochondrial/genetics, Female, Genes, Neoplasm/genetics, High-Throughput Screening Assays, Humans, Middle Aged, Mitochondria/genetics, Mutation/genetics, Nucleic Acid Conformation, PTEN Phosphohydrolase/genetics, Promoter Regions, Genetic/genetics, Proto-Oncogene Proteins c-mdm2/genetics, Signal Transduction/genetics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tumor Suppressor Protein p14ARF/genetics, Tumor Suppressor Protein p53/genetics
Pubmed
Web of science
Open Access
Yes
Create date
23/12/2010 17:59
Last modification date
16/10/2019 7:08
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