Abstract
IntroductionIn 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.MethodsWe 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).ResultsOur 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.ConclusionUsing 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.
Highlights
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
Previous global gene expression profiling studies of breast carcinomas have identified at least five distinct subtypes of breast cancer [9,10,11,12,13] with specific patterns of Copy Number Aberrations (CNA) that can define genetic events associated with different expression subtypes [14,15]
In order to test the hypothesis that primary breast cancer genomes contain areas of small-scale copy number gains and losses, termed micro-aberrations, we designed a custom, highresolution, high-density, comparative genomic hybridization tiling array (HD-aCGH) with an average probe spacing of 200 base pairs, and which was focused on 128 selected genes (Table S2)
Summary
The basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. It has been shown that alterations on a genomic DNA level are likely to cause associated changes in gene expression [7,8]. Previous global gene expression profiling studies of breast carcinomas have identified at least five distinct subtypes of breast cancer [9,10,11,12,13] with specific patterns of Copy Number Aberrations (CNA) that can define genetic events associated with different expression subtypes [14,15]. The interplay between genomic DNA changes and gene expression is something that can yield much information about the underlying processes that contribute to breast cancer formation and development. Continued investigation of copy number abnormalities in breast cancer is likely to yield additional insights into the pathogenesis of the disease
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