Dataset Information

Identification and functional analysis of 9p24 amplified genes in human breast cancer.

ABSTRACT: Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2?Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16(INK4a), p21(Waf1/Cip1) and p27(Kip1). Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.

SUBMITTER: Wu J

PROVIDER: S-EPMC3886828 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification and functional analysis of 9p24 amplified genes in human breast cancer.

Wu J J Liu S S Liu G G Dombkowski A A Abrams J J Martin-Trevino R R Wicha M S MS Ethier S P SP Yang Z-Q ZQ

Oncogene 20110613 3

Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a ...[more]

PMID: 21666724

Similar Datasets

Project description:The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the driver mutations, genetic backgrounds, and key pathways activated across cancer types. Analysis of TCGA datasets have mostly focused on somatic mutations and translocations, with less emphasis placed on gene amplifications. Here we describe a bioinformatics screening strategy to identify putative cancer driver genes amplified across TCGA datasets. We carried out GISTIC2 analysis of TCGA datasets spanning 16 cancer subtypes and identified 486 genes that were amplified in two or more datasets. The list was narrowed to 75 cancer-associated genes with potential "druggable" properties. The majority of the genes were localized to 14 amplicons spread across the genome. To identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 42 putative cancer driver genes linked to diverse oncogenic processes. Oncogenic activity was further validated by siRNA/shRNA knockdown and by referencing the Project Achilles datasets. The amplified genes represented a number of gene families, including epigenetic regulators, cell cycle-associated genes, DNA damage response/repair genes, metabolic regulators, and genes linked to the Wnt, Notch, Hedgehog, JAK/STAT, NF-KB and MAPK signaling pathways. Among the 42 putative driver genes were known driver genes, such as EGFR, ERBB2 and PIK3CA. Wild-type KRAS was amplified in several cancer types, and KRAS-amplified cancer cell lines were most sensitive to KRAS shRNA, suggesting that KRAS amplification was an independent oncogenic event. A number of MAP kinase adapters were co-amplified with their receptor tyrosine kinases, such as the FGFR adapter FRS2 and the EGFR family adapters GRB2 and GRB7. The ubiquitin-like ligase DCUN1D1 and the histone methyltransferase NSD3 were also identified as novel putative cancer driver genes. We discuss the patient tailoring implications for existing cancer drug targets and we further discuss potential novel opportunities for drug discovery efforts.

Project description:PurposeAmplified in breast cancer 1 (AIB1) expression is known to be involved in the initiation and progression of malignant breast cancer (BC), but its prognostic role remains uncertain. This meta-analysis assessed reported studies to evaluate this relationship.MethodsElectronic databases were systematically reviewed to collect eligible studies using pre-established criteria. Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were pooled to estimate the impact of AIB1 protein expression on overall survival (OS) and clinicopathologic properties of BC cases.ResultsNine eligible studies, including 6774 patients, were finally assessed by the current clinical meta-analysis. AIB1 positivity correlated with reduced OS (pooled HR = 1.409, 95% CI 1.159-1.714, P = .001). AIB1 overexpression also impacted prognosis as shown by univariate (pooled HR = 1.420, 95% CI 1.154-1.747, P = .001) and multivariate (pooled HR = 1.446, 95% CI 1.099-1.956; P = .009) analyses. Notably, subgroup analyses also revealed that AIB1 overexpression was associated with poor OS in some subgroups, such as ER-positive group (pooled HR = 1.511, 95% CI 1.138-2.006, P = .004), ER-positive without tamoxifen administration group (pooled HR = 2.338, 95% CI 1.489-3.627, P < .001), and premenopausal women group (pooled HR = 1.715, 95% CI 1.231-2.390, P = .001). Additionally, high AIB1 protein levels were associated with HER2 positivity (pooled OR = 0.331, 95% CI 0.245-0.448; P < .001), poorly differentiated histological grade (pooled OR = 0.377, 95% CI 0.317-0.448; P < .001), high Ki67 (pooled OR = 0.501, 95% CI 0.410-0.612; P < .001), presence of lymph node metastases (pooled OR = 0.866, 95% CI 0.752-0.997; P = .045), and absence of progesterone receptor (pooled OR = 1.447, 95% CI 1.190-1.759; P < .001).ConclusionsThis analysis demonstrated that AIB1 overexpression is related to aggressive phenotypes and unfavorable clinical outcomes in BC, and might involve in tamoxifen resistance. AIB1 may be a new prognostic biomarker and therapeutic target in BC.

Project description:Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC), and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential. Anthracycline drugs are typically used as the first-line clinical treatment for basal-like breast cancer subtypes. However, certain patients develop drug resistance following chemotherapy, which can lead to disease relapse and death. Even among patients with basal-like breast cancer, there can be significant molecular differences, and it is difficult to identify specific drug resistance proteins in any given patient using conventional variance testing methods. Therefore, we designed a new method for identifying drug resistance genes. Subgroups, personalized biomarkers, and therapy targets were identified using cluster analysis of differentially expressed genes. We found that basal-like breast cancer could be further divided into at least four distinct subgroups, including two groups at risk for drug resistance and two groups characterized by sensitivity to pharmacotherapy. Based on functional differences among these subgroups, we identified nine biomarkers related to drug resistance: SYK, LCK, GAB2, PAWR, PPARG, MDFI, ZAP70, CIITA and ACTA1. Finally, based on the deviation scores of the examined pathways, 16 pathways were shown to exhibit varying degrees of abnormality in the various subgroups, indicating that patients with different subtypes of basal-like breast cancer can be characterized by differences in the functional status of these pathways. Therefore, these nine differentially expressed genes and their associated functional pathways should provide the basis for novel personalized clinical treatments of basal-like breast cancer.

Dataset Information

Identification and functional analysis of 9p24 amplified genes in human breast cancer.

Publications

Identification and functional analysis of 9p24 amplified genes in human breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets