Genomic Differences Between Estrogen Receptor (ER)-Positive and ER-Negative Human Breast Carcinoma Identified by Single Nucleotide Polymorphism Array Comparative Genome Hybridization Analysis

Fired Hutchinson Cancer Research Center, Seattle, WA 98109-1023, USA.
Cancer (Impact Factor: 4.89). 05/2011; 117(10):2024-34. DOI: 10.1002/cncr.25770
Source: PubMed


Estrogen receptor (ER) remains one of the most important biomarkers for breast cancer subtyping and prognosis, and comparative genome hybridization has greatly contributed to the understanding of global genetic imbalance. The authors used single-nucleotide polymorphism (SNP) arrays to compare overall copy number aberrations (CNAs) as well as loss of heterozygosity (LOH) of the entire human genome in ER-positive and ER-negative breast carcinomas.
DNA was extracted from frozen tumor sections of 21 breast carcinoma specimens and analyzed with a proprietary 50K XbaI SNP array. Copy number and LOH probability values were derived for each sample. Data were analyzed using bioinformatics and computational software, and permutation tests were used to estimate the significance of these values.
There was a global increase in CNAs and LOH in ER-negative relative to ER-positive cancers. Gain of the long arm of chromosome 1 (1q) and 8q were the most obvious changes common in both subtypes: An increase in the chromosome 1 short arm (1p)/1q ratio was observed in ER-negative samples, and an increased 16p/16q ratio was observed in ER-positive samples. Significant CNAs (adjusted P<.05) in ER-negative relative to ER-positive tumors included 5q deletion, loss of 15q, and gain of 2p and 21q. Copy-neutral LOH (cnLOH) common to both ER-positive and ER-negative samples included 9p21, the p16 tumor suppressor locus, and 4q13, the RCHY1 (ring finger and CHY zinc finger domain-containing 1) oncogene locus. Of particular interest was an enrichment of 17q LOH among the ER-negative tumors, potentially suggesting breast cancer 1 gene (BRCA1) mutations.
SNP array detected both genetic imbalances and cnLOH and was capable of discriminating ER-negative breast cancer from ER-positive breast cancer.

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    • "Specifically, we found strong and consistent enrichment for the estrogen receptor binding around somatic translocations. Patterns were similar for both ER-positive and ER-negative breast cancers, consistent with previous results [35-37]. To examine possible interactions between ESR1 and other transcription factors, for each of the ESR1 experiment, we identified somatic breakpoints within 50 kb of an ESR1 binding site, and then identified genes within 10 kb of such breakpoints. "
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    ABSTRACT: Background Interactions between the epigenome and structural genomic variation are potentially bi-directional. In one direction, structural variants may cause epigenomic changes in cis. In the other direction, specific local epigenomic states such as DNA hypomethylation associate with local genomic instability. Methods To study these interactions, we have developed several tools and exposed them to the scientific community using the Software-as-a-Service model via the Genboree Workbench. One key tool is Breakout, an algorithm for fast and accurate detection of structural variants from mate pair sequencing data. Results By applying Breakout and other Genboree Workbench tools we map breakpoints in breast and prostate cancer cell lines and tumors, discriminate between polymorphic breakpoints of germline origin and those of somatic origin, and analyze both types of breakpoints in the context of the Human Epigenome Atlas, ENCODE databases, and other sources of epigenomic profiles. We confirm previous findings that genomic instability in human germline associates with hypomethylation of DNA, binding sites of Suz12, a key member of the PRC2 Polycomb complex, and with PRC2-associated histone marks H3K27me3 and H3K9me3. Breakpoints in germline and in breast cancer associate with distal regulatory of active gene transcription. Breast cancer cell lines and tumors show distinct patterns of structural mutability depending on their ER, PR, or HER2 status. Conclusions The patterns of association that we detected suggest that cell-type specific epigenomes may determine cell-type specific patterns of selective structural mutability of the genome.
    BMC Bioinformatics 05/2014; 15(Suppl 7):S2. DOI:10.1186/1471-2105-15-S7-S2 · 2.58 Impact Factor
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    • "The long arm of chromosome 1 (1q) is known for its frequent copy number gains whereas 1p region often shows copy number loss [11]. The most interesting aspect of 1q gain in breast cancer is its prevalence in almost all types of breast cancer like Estrogen Receptor (ER) positive, ER negative [12], Luminal A [13], Ductal carcinoma in situ (DCIS) and Invasive ductal carcinoma (IDC) [14]. Recurrent 1q gain in breast cancers [11,15], and combined investigations of chromosome 1q gain with other amplifications have been reported [16,17]. "
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    ABSTRACT: Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA-drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors.
    PLoS ONE 10/2013; 8(10):e77553. DOI:10.1371/journal.pone.0077553 · 3.23 Impact Factor
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    • "For instance, BRCA-associated breast and ovarian cancers demonstrate high levels of CIN, whereas lung cancer in smokers and never smokers differs in the extent of segmental alterations and subsequently, genome instability [83–86]. Moreover, specific subtypes of breast, ovarian, and lung cancers exhibit distinct patterns of alterations; the basal-like subtype of breast cancers (typically estrogen receptor-negative) have greater CIN than luminal subtypes, while type II high-grade serous ovarian carcinomas have greater CIN than type I serous ovarian cancers [87, 88]. In lung cancer, adenocarcinoma and squamous cell carcinoma demonstrate distinct patters of genomic alterations, and within lung adenocarcinoma, the magnoid subtype displays higher CIN than other adenocarcinoma subtypes [89, 90]. "
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    ABSTRACT: Genomic instability is a hallmark of cancer that leads to an increase in genetic alterations, thus enabling the acquisition of additional capabilities required for tumorigenesis and progression. Substantial heterogeneity in the amount and type of instability (nucleotide, microsatellite, or chromosomal) exists both within and between cancer types, with epithelial tumors typically displaying a greater degree of instability than hematological cancers. While high-throughput sequencing studies offer a comprehensive record of the genetic alterations within a tumor, detecting the rate of instability or cell-to-cell viability using this and most other available methods remains a challenge. Here, we discuss the different levels of genomic instability occurring in human cancers and touch on the current methods and limitations of detecting instability. We have applied one such approach to the surveying of public tumor data to provide a cursory view of genome instability across numerous tumor types.
    CANCER AND METASTASIS REVIEW 05/2013; 32(3-4). DOI:10.1007/s10555-013-9429-5 · 7.23 Impact Factor
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