Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer.
In breast cancer, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations, as shown by a previously describ...
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doaj-4cc206c14ad04c6aa01fbc58d2a78cda2020-11-25T02:33:33ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01712e5171910.1371/journal.pone.0051719Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer.Hann-Hsiang ChaoXiaping HeJoel S ParkerWei ZhaoCharles M PerouIn breast cancer, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations, as shown by a previously described micro-deletion event in the PTEN gene in the Basal-like SUM149 breast cancer cell line.We sought to identify if small regions of genomic DNA copy number changes exist by using a high density, gene-centric Comparative Genomic Hybridizations (CGH) array on cell lines and primary tumors. A custom tiling array for CGH (244,000 probes, 200 bp tiling resolution) was created to identify small regions of genomic change, which was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments were called micro-aberrations (<64 contiguous probes, ~ 15 kb).Our data showed that primary tumor breast cancer genomes frequently contained many small-scale copy number gains and losses, termed micro-aberrations, most of which are undetectable using typical-density genome-wide aCGH arrays. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5' regions of the affected genes, including the promoter region, and high frequency of micro-aberrations was associated with poor survival.Using a high-probe-density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that can contribute to gene inactivation. These events may contribute to tumor formation through mechanisms not detected using conventional DNA copy number analyses.http://europepmc.org/articles/PMC3524128?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hann-Hsiang Chao Xiaping He Joel S Parker Wei Zhao Charles M Perou |
spellingShingle |
Hann-Hsiang Chao Xiaping He Joel S Parker Wei Zhao Charles M Perou Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer. PLoS ONE |
author_facet |
Hann-Hsiang Chao Xiaping He Joel S Parker Wei Zhao Charles M Perou |
author_sort |
Hann-Hsiang Chao |
title |
Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer. |
title_short |
Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer. |
title_full |
Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer. |
title_fullStr |
Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer. |
title_full_unstemmed |
Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer. |
title_sort |
micro-scale genomic dna copy number aberrations as another means of mutagenesis in breast cancer. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
In breast cancer, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations, as shown by a previously described micro-deletion event in the PTEN gene in the Basal-like SUM149 breast cancer cell line.We sought to identify if small regions of genomic DNA copy number changes exist by using a high density, gene-centric Comparative Genomic Hybridizations (CGH) array on cell lines and primary tumors. A custom tiling array for CGH (244,000 probes, 200 bp tiling resolution) was created to identify small regions of genomic change, which was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments were called micro-aberrations (<64 contiguous probes, ~ 15 kb).Our data showed that primary tumor breast cancer genomes frequently contained many small-scale copy number gains and losses, termed micro-aberrations, most of which are undetectable using typical-density genome-wide aCGH arrays. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5' regions of the affected genes, including the promoter region, and high frequency of micro-aberrations was associated with poor survival.Using a high-probe-density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that can contribute to gene inactivation. These events may contribute to tumor formation through mechanisms not detected using conventional DNA copy number analyses. |
url |
http://europepmc.org/articles/PMC3524128?pdf=render |
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