Major chromosomal breakpoint intervals in breast cancer co-localize with differentially methylated regions

Tang, M. H., Varadan, V., Kamalakaran, S., Zhang, M. Q., Dimitrova, N., Hicks, J. (2012) Major chromosomal breakpoint intervals in breast cancer co-localize with differentially methylated regions. Frontiers in Oncology, 2. p. 197. ISSN 2234-943X (Electronic)2234-943X (Linking)

[img]
Preview
PDF
Zhang and Hicks Frontiers in Oncology 2012.pdf

Download (1246Kb) | Preview
URL: http://www.ncbi.nlm.nih.gov/pubmed/23293768
DOI: 10.3389/fonc.2012.00197

Abstract

Solid tumors exhibit chromosomal rearrangements resulting in gain or loss of multiple chromosomal loci (copy number variation, or CNV), and translocations that occasionally result in the creation of novel chimeric genes. In the case of breast cancer, although most individual tumors each have unique CNV landscape, the breakpoints, as measured over large datasets, appear to be non-randomly distributed in the genome. Breakpoints show a significant regional concentration at genomic loci spanning perhaps several megabases. The proximal cause of these breakpoint concentrations is a subject of speculation, but is, as yet, largely unknown. To shed light on this issue, we have performed a bio-statistical analysis on our previously published data for a set of 119 breast tumors and normal controls (Wiedswang et al., 2003), where each sample has both high-resolution CNV and methylation data. The method examined the distribution of closeness of breakpoint regions with differentially methylated regions (DMR), coupled with additional genomic parameters, such as repeat elements and designated "fragile sites" in the reference genome. Through this analysis, we have identified a set of 93 regional loci called breakpoint enriched DMR (BEDMRs) characterized by altered DNA methylation in cancer compared to normal cells that are associated with frequent breakpoint concentrations within a distance of 1 Mb. BEDMR loci are further associated with local hypomethylation (66%), concentrations of the Alu SINE repeats within 3 Mb (35% of the cases), and tend to occur near a number of cancer related genes such as the protocadherins, AKT1, DUB3, GAB2. Furthermore, BEDMRs seem to deregulate members of the histone gene family and chromatin remodeling factors, e.g., JMJD1B, which might affect the chromatin structure and disrupt coordinate signaling and repair. From this analysis we propose that preference for chromosomal breakpoints is related to genome structure coupled with alterations in DNA methylation and hence, chromatin structure, associated with tumorigenesis.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function
CSHL Authors:
Communities: CSHL labs > Hicks lab
CSHL labs > Zhang lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date Deposited: 06 Feb 2014 17:49
Last Modified: 15 Oct 2015 15:14
PMCID: PMC3530719
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29484

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving