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Genome-wide multi-omics profiling reveals extensive genetic complexity in 8p11-p12 amplified breast carcinomas [RNA-seq]

ABSTRACT: Transcriptomic profiling of human breast tumors using RNA sequencing

ORGANISM(S): Homo sapiens

PROVIDER: GSE100799 | GEO | 2019/04/17

REPOSITORIES: GEO

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Genome-wide multi-omics profiling reveals extensive genetic complexity in 8p11-p12 amplified breast carcinomas

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-03-31 | GSE97293 | GEO

Genome-wide multi-omics profiling reveals extensive genetic complexity in 8p11-p12 amplified breast carcinomas [aCGH]

Project description:DNA copy number alterations play an important role in cancer development and progression by changing the transcriptional levels of key cancer-related genes. However, gene expression patterns may also be affected by other mechanisms. To test these basic principles, we have applied genome-wide screening techniques to 53 invasive breast tumors with array comparative genomic hybridization and gene expression microarrays to assess the direct effect of gene dosage on gene expression levels and independently to test the effect of other mechanisms on transcriptional levels. Low-level gain, high-level gain/amplification, heterozygous loss and homozygous deletion (henceforth referred to as gain, amplification, loss and deletion) were defined as log2 ratio thresholds set at +0.2, ≥+0.5, -0.2 and ≤-1.0, respectively.

2017-03-31 | GSE97292 | GEO

Genome-wide multi-omics profiling reveals extensive genetic complexity in 8p11-p12 amplified breast carcinomas [expression]

Project description:Transcriptomic profiling of human breast tumors. Genomic and expression profiling using 38K BAC array-CGH and Illumina HT-12 beadchips were performed on 53 invasive breast tumors to assess the impact of gene dosage on gene expression patterns and the effect of other mechanisms on transcriptional levels. Array-CGH results was validated by FISH using tumors showing 8p11-p12 DNA amplification and expression profiling was confirmed using qPCR for 11 transcripts. Low-level gain, high-level gain/amplification, heterozygous loss and homozygous deletion (henceforth referred to as gain, amplification, loss and deletion) were defined as log2 ratio thresholds set at +0.2, >= +0.5, -0.2 and <=-1.0, respectively.

2017-03-30 | GSE97177 | GEO

Genome-wide multi-omics profiling reveals extensive genetic complexity in 8p11-p12 amplified breast carcinomas [SNP_genotyping]

Project description:SNP genotyping of human breast tumors

2019-04-17 | GSE100529 | GEO

Genome-wide multi-omics profiling reveals extensive genetic complexity in 8p11-p12 amplified breast carcinomas

Project description:Genome-wide multi-omics profiling reveals extensive genetic complexity in 8p11-p12 amplified breast carcinomas

| PRJNA381213 | ENA

Genome-wide multi-omics profiling of the 8p11-p12 amplicon in breast carcinoma.

Project description:Genomic instability contributes to the neoplastic phenotype by deregulating key cancer-related genes, which in turn can have a detrimental effect on patient outcome. DNA amplification of the 8p11-p12 genomic region has clinical and biological implications in multiple malignancies, including breast carcinoma where the amplicon has been associated with tumor progression and poor prognosis. However, oncogenes driving increased cancer-related death and recurrent genetic features associated with the 8p11-p12 amplicon remain to be identified. In this study, DNA copy number and transcriptome profiling data for 229 primary invasive breast carcinomas (corresponding to 185 patients) were evaluated in conjunction with clinicopathological features to identify putative oncogenes in 8p11-p12 amplified samples. Illumina paired-end whole transcriptome sequencing and whole-genome SNP genotyping were subsequently performed on 23 samples showing high-level regional 8p11-p12 amplification to characterize recurrent genetic variants (SNPs and indels), expressed gene fusions, gene expression profiles and allelic imbalances. We now show previously undescribed chromothripsis-like patterns spanning the 8p11-p12 genomic region and allele-specific DNA amplification events. In addition, recurrent amplification-specific genetic features were identified, including genetic variants in the HIST1H1E and UQCRHL genes and fusion transcripts containing MALAT1 non-coding RNA, which is known to be a prognostic indicator for breast cancer and stimulated by estrogen. In summary, these findings highlight novel candidate targets for improved treatment of 8p11-p12 amplified breast carcinomas.

| S-EPMC5963621 | biostudies-literature

Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas.

Project description:Genetic and epigenetic (DNA methylation, histone modifications, microRNA expression) crosstalk promotes inactivation of tumor suppressor genes or activation of oncogenes by gene loss/hypermethylation or duplications/hypomethylation, respectively. The 8p11-p12 chromosomal region is a hotspot for genomic aberrations (chromosomal rearrangements, amplifications and deletions) in several cancer forms, including breast carcinoma where amplification has been associated with increased proliferation rates and reduced patient survival. Here, an integrative genomics screen (DNA copy number, transcriptional and DNA methylation profiling) performed in 229 primary invasive breast carcinomas identified substantial coamplification of the 8p11-p12 genomic region and the MYC oncogene (8q24.21), as well as aberrant methylation and transcriptional patterns for several genes spanning the 8q12.1-q24.22 genomic region (ENPP2, FABP5, IMPAD1, NDRG1, PLEKHF2, RRM2B, SQLE, TAF2, TATDN1, TRPS1, VPS13B). Taken together, our findings suggest that MYC activity and aberrant DNA methylation may also have a pivotal role in the aggressive tumor phenotype frequently observed in breast carcinomas harboring 8p11-p12 regional amplification.

| S-EPMC4038389 | biostudies-literature

Transforming properties of 8p11-12 amplified genes in human breast cancer.

Project description:Amplification of the 8p11-12 region has been found in about 15% of human breast cancers and is associated with poor prognosis. Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon to identify candidate oncogenes in breast cancer. We identified 21 candidate genes and provided evidence that three genes, namely, LSM-1, TC-1, and BAG4, have transforming properties when overexpressed. In the present study, we systematically investigated the transforming properties of 13 newly identified 8p11-12 candidate oncogenes in vitro. WHSC1L1, DDHD2, and ERLIN2 were most potently transforming oncogenes based on the number of altered phenotypes expressed by the cells. WHSC1L1 contains a PWWP-domain that is a methyl-lysine recognition motif involved in histone code modification and epigenetic regulation of gene expression. Knockdown of WHSC1L1 in 8p11-12-amplified breast cancer cells resulted in profound loss of growth and survival of these cells. Further, we identified several WHSC1L1 target genes, one of which is iroquois homeobox 3 gene (IRX3), a member of the Iroquois homeobox transcription factor family.

| S-EPMC3089754 | biostudies-literature

KAT6A, a chromatin modifier from the 8p11-p12 amplicon is a candidate oncogene in luminal breast cancer.

Project description:The chromosome 8p11-p12 amplicon is present in 12% to 15% of breast cancers, resulting in an increase in copy number and expression of several chromatin modifiers in these tumors, including KAT6A. Previous analyses in SUM-52 breast cancer cells showed amplification and overexpression of KAT6A, and subsequent RNAi screening identified KAT6A as a potential driving oncogene. KAT6A is a histone acetyltransferase previously identified as a fusion partner with CREB binding protein in acute myeloid leukemia. Knockdown of KAT6A in SUM-52 cells, a luminal breast cancer cell line harboring the amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A, however, did not exhibit slower growth with knockdown of KAT6A. SUM-52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to controls, suggesting a possible role for KAT6A in self-renewal. Previous data from our laboratory identified FGFR2 as a driving oncogene in SUM-52 cells. The colony forming efficiency of SUM-52 KAT6A knockdown cells in the presence of FGFR inhibition was significantly reduced compared to cells with KAT6A knockdown only. These data suggest that KAT6A may be a novel oncogene in breast cancers bearing the 8p11-p12 amplicon. While there are other putative oncogenes in the amplicon, the identification of KAT6A as a driving oncogene suggests that chromatin-modifying enzymes are a key class of oncogenes in these cancers, and play an important role in the selection of this amplicon in luminal B breast cancers.

| S-EPMC4234874 | biostudies-literature

Transforming properties of 8p11-12 amplified genes in human breast cancer

Project description:MCF10A cells was transduced with WHSC1L1 short isoform lentiviral expression vector. Expression profiling of MCF10A-WHSC1L1 cells, and breast cancer SUM-44 cells were performed

2010-08-21 | GSE23734 | GEO

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