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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Formalin-fixed paraffin-embedded (FFPE) archival clinical specimens are invaluable in discovery of prognostic and therapeutic targets for diseases such as cancer. However, the suitability of FFPE-derived genetic material for array-based comparative genomic hybridization (array-CGH) studies is underexplored. In this study, genetic profiles of matched FFPE and fresh-frozen specimens were examined to investigate DNA integrity differences between these sample types and determine the impact this may have on genetic profiles. Genomic DNA was extracted from three patient-matched FFPE and fresh-frozen clinical tissue samples. T47D breast cancer control cells were also grown in culture and processed to yield a fresh T47D sample, a fresh-frozen T47D sample and a FFPE T47D sample. DNA was extracted from all the samples; array-CGH conducted and genetic profiles of matched samples were then compared. A loss of high molecular weight DNA was observed in the FFPE clinical tissues and FFPE T47D samples. A dramatic increase in absolute number of genetic alterations was observed in all FFPE tissues relative to matched fresh-frozen counterparts. In future, alternative fixation and tissue-processing procedures, and/or new DNA extraction and CGH profiling protocols, may be implemented, enabling identification of changes involved in disease progression using stored clinical specimens.
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PMID:Formalin-fixed paraffin-embedded clinical tissues show spurious copy number changes in array-CGH profiles. 1793 7

Loss of H4 lysine 16 (H4K16) acetylation was shown to be a common feature in human cancer. However, it remained unclear which enzyme is responsible for the loss of this modification. Having recently identified the histone acetyltransferase human MOF (hMOF) to be required for bulk H4K16 acetylation, here we examined the involvement of hMOF expression and H4K16 acetylation in breast cancer and medulloblastoma. Analysis of a recent mRNA expression profiling study in breast cancer (n = 100 cases) and an array-CGH screen in medulloblastomas (n = 102 cases), revealed downregulation in 40% and genomic loss in 11% of cases, respectively. We investigated hMOF protein expression as well as H4K16 acetylation in large series of primary breast carcinomas (n = 298) and primary medulloblastomas (n = 180) by immunohistochemistry. In contrast to nontransformed control tissues, significant fractions of both primary breast carcinomas and medulloblastomas showed markedly reduced hMOF mRNA and protein expression. In addition, hMOF protein expression tightly correlated with acetylation of H4K16 in all tested samples. For medulloblastoma, downregulation of hMOF protein expression was associated with lower survival rates identifying hMOF as an independent prognostic marker for clinical outcome in univariate as well as multivariate analyses.
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PMID:The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. 1805 15

Five breast cancer subtypes have been described in sporadic breast cancer (SBC) using expression arrays: basal-like, ERBB2, normal breast-like, luminal A and B. These molecular subtypes show different genomic aberration patterns (GAPs). Recently, our group described these breast cancer subtypes in 50 non-BRCA1/2 familial tumors using immunohistochemistry assays. We extended this study to the other classes of familial breast cancer (FBC), including 62 tumors (18 BRCA1, 16 BRCA2 and 28 non-BRCA1/2), with the same panel of 25 immunohistochemical (IHC) markers and histological grade obtaining a similar classification. We combined these data with results generated by a 1 Mb BAC array-based CGH study to evaluate the genomic aberrations of each group. We found that BRCA1-related tumors are preferentially basal-like, whereas non-BRCA1/2 familial tumors are mainly luminal A subtype. We described distinct GAPs related to each IHC subtype. Basal tumors had a greater number of gains/losses, while luminal B tumors had more high-level DNA amplifications. Our data are similar to those obtained in SBC studies, highlighting the existence of distinct genetic pathways of tumor evolution, common to both SBC and FBC.
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PMID:Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes. 1807 13

Only few selected cancer cells drive tumor progression and are responsible for therapy resistance. Their specific genomic characteristics, however, are largely unknown because high-resolution genome analysis is currently limited to DNA pooled from many cells. Here, we describe a protocol for array comparative genomic hybridization (array CGH), which enables the detection of DNA copy number changes in single cells. Combining a PCR-based whole genome amplification method with arrays of highly purified BAC clones we could accurately determine known chromosomal changes such as trisomy 21 in single leukocytes as well as complex genomic imbalances of single cell line cells. In single T47D cells aberrant regions as small as 1-2 Mb were identified in most cases when compared to non-amplified DNA from 10(6) cells. Most importantly, in single micrometastatic cancer cells isolated from bone marrow of breast cancer patients, we retrieved and confirmed amplifications as small as 4.4 and 5 Mb. Thus, high-resolution genome analysis of single metastatic precursor cells is now possible and may be used for the identification of novel therapy target genes.
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PMID:High-resolution array comparative genomic hybridization of single micrometastatic tumor cells. 1834 24

The central dogma of molecular biology relates DNA with mRNA. Array CGH measures DNA copy number and gene expression microarrays measure the amount of mRNA. Methods that integrate data from these two platforms may uncover meaningful biological relationships that further our understanding of cancer. We develop nonparametric tests for the detection of copy number induced differential gene expression. The tests incorporate the uncertainty of the calling of genomic aberrations. The test is preceded by a "tuning algorithm" that discards certain genes to improve the overall power of the false discovery rate selection procedure. Moreover, the test statistics are "shrunken" to borrow information across neighboring genes that share the same array CGH signature. For each gene we also estimate its effect, its amount of differential expression due to copy number changes, and calculate the coefficient of determination. The method is illustrated on breast cancer data, in which it confirms previously reported findings, now with a more profound statistical underpinning.
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PMID:Nonparametric testing for DNA copy number induced differential mRNA gene expression. 1847 79

Breast cancer accounts for over 20% of all female cancers. A positive family history remains one of the most important risk factors for the disease, with first-degree relatives of patients having a twofold elevated risk. Known breast cancer susceptibility genes such as BRCA1 and BRCA2 explain only 20-25% of this risk, suggesting the existence of other breast cancer susceptibility genes. Here, we report the results of a genome-wide linkage scan in 55 high-risk Dutch breast cancer families with no mutations in BRCA1 and BRCA2. Twenty-two of these families were also part of a previous linkage study by the Breast Cancer Linkage Consortium. In addition, we performed CGH analyses in 61 tumors of these families and 31 sporadic tumors. Three regions were identified with parametric HLOD scores >1, and three with nonparametric LOD scores >1.5. Upon further marker genotyping for the candidate loci, and the addition of another 30 families to the analysis, only the locus on chromosome 9 (9q21-22, marker D9S167) remained significant, with a nonparametric multipoint LOD score of 3.96 (parametric HLOD 0.56, alpha = 0.18). With CGH analyses we observed preferential copy number loss at BAC RP11-276H19, containing D9S167 in familial tumors as compared to sporadic tumors (P < 0.001). Five candidate genes were selected from the region around D9S167 and their coding regions subjected to direct sequence analysis in 16 probands. No clear pathogenic mutations were found in any of these genes.
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PMID:Genome-wide linkage scan in Dutch hereditary non-BRCA1/2 breast cancer families identifies 9q21-22 as a putative breast cancer susceptibility locus. 1866 45

Array comparative genomic hybridization (array CGH) is widely used for studying chromosomal copy number aberrations (CNAs) on a genome-wide and high-resolution scale in heritable disorders and cancers. The aim of this study was to test if the separate channels of dual channel arrays can be interchanged (across array) to either make array CGH more sensitive and cost effective and/or to generate profiles of CNAs and copy number variations (CNVs). Therefore the BT474 breast cancer cell line was compared with a mix of normal reference DNAs hybridized on different arrays and days and DNA copy number profiles were evaluated. Quality was assessed, using regular dual channel array CGH as a standard, using four quality measures, i.e., the median absolute deviation value of chromosome 2, the amplitude of the ERBB2 gene amplification, a deletion on chromosome 9, and the deflection on chromosome 8. The quality of the across array CGH profiles matched or even surpassed the quality of regular dual channel array CGH. In addition, this across array approach was tested for genomic DNA derived from formalin-fixed paraffin-embedded tumors tissue samples, resulting in high-quality copy number profiles, comparable to regular dual channel arrays. Finally, we demonstrated this approach to obtain both CNA and CNV profiles. In summary, across array CGH avoids redundant hybridizations of the same reference material in every experiment either allowing hybridization of two test samples on one array or producing both CNA and CNV profiles simultaneously.
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PMID:Across array comparative genomic hybridization: a strategy to reduce reference channel hybridizations. 1866 53

Intratumor genetic heterogeneity, a well-known characteristic of numerous cancers, often confounds a precise diagnosis and leads to therapy resistance. This study deals with such chromosomal variability, which may be due to an inherent genetic instability affecting heterogeneity and clonal effects. Subpopulations of the breast cancer cell line MDA-MB-468 were isolated according to epidermal growth factor receptor (EGFR) expression by FACS. Whole genome profiling (CGH; mapping arrays) and determination of egfr gene amplification (fluorescence in situ hybridisation, FISH; qPCR) were done directly after sorting or after several passages of cell culture. Subpopulations differed in the amplification of the egfr-locus 7p11-14 showing egfr gene amplification rates of up to 60-fold in high-level expressing populations and less than 2-fold in low-level expressing populations. However, after several passages the original low-level cells showed a new amplification of the egfr gene, which was as heterogeneous as the original amplification detected in MDA-MB-468. Additional, spontaneously expressed fragile sites could be shown in FISH analyses which may affect cell culture heterogeneity. Understanding the precise chromosomal process would clarify mechanisms in vivo and improve both diagnosis and therapy of corresponding cancers.
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PMID:[Different coexisting genotypes in the breast cancer cell line MDA-MB-468]. 1875 81

65-80% of the patients with breast cancer might not benefit from the adjuvant therapy they receive based on 'classical' markers used for the selection for adjuvant therapy. Therefore it is necessary to develop new markers that are able to tailor treatment for an individual patient. A number of microarray methods have been developed in recent years to accommodate this search for new factors that determine breast cancer progression. We give an overview of the most commonly used microarray methods to identify tumour progression markers (oligo- or cDNA arrays, CGH arrays, PCR arrays, and tissue microarrays). Their applications will be illustrated using the most influential examples from literature. The potentials, limitations and the related statistical analyses of each method are discussed. We conclude that microarray studies have led to an increase in the understanding of the complexity and diversity of breast carcinoma and have provided clinical relevant subgroups of breast cancer that may benefit from patient tailored treatment. Still, more extensive external validation and long-term follow-up will be necessary before such assays can be implemented into routine clinical practice. Most likely, these novel prognostic indicators will be complementary to the already available classical prognostic factors.
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PMID:Microarray methods to identify factors determining breast cancer progression: potentials, limitations, and challenges. 1884 65

By applying a method that combines end-sequence profiling and massively parallel sequencing, we obtained a sequence-level map of chromosomal aberrations in the genome of the MCF-7 breast cancer cell line. A total of 157 distinct somatic breakpoints of two distinct types, dispersed and clustered, were identified. A total of 89 breakpoints are evenly dispersed across the genome. A majority of dispersed breakpoints are in regions of low copy repeats (LCRs), indicating a possible role for LCRs in chromosome breakage. The remaining 68 breakpoints form four distinct clusters of closely spaced breakpoints that coincide with the four highly amplified regions in MCF-7 detected by array CGH located in the 1p13.1-p21.1, 3p14.1-p14.2, 17q22-q24.3, and 20q12-q13.33 chromosomal cytobands. The clustered breakpoints are not significantly associated with LCRs. Sequences flanking most (95%) breakpoint junctions are consistent with double-stranded DNA break repair by nonhomologous end-joining or template switching. A total of 79 known or predicted genes are involved in rearrangement events, including 10 fusions of coding exons from different genes and 77 other rearrangements. Four fusions result in novel expressed chimeric mRNA transcripts. One of the four expressed fusion products (RAD51C-ATXN7) and one gene truncation (BRIP1 or BACH1) involve genes coding for members of protein complexes responsible for homology-driven repair of double-stranded DNA breaks. Another one of the four expressed fusion products (ARFGEF2-SULF2) involves SULF2, a regulator of cell growth and angiogenesis. We show that knock-down of SULF2 in cell lines causes tumorigenic phenotypes, including increased proliferation, enhanced survival, and increased anchorage-independent growth.
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PMID:A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. 1905 96


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