Dataset Information

Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma.

ABSTRACT: A genomewide technology, digital karyotyping, was used to identify subchromosomal alterations in ovarian cancer. Amplification at 11q13.5 was found in three of seven ovarian carcinomas, and amplicon mapping delineated a 1.8-Mb core of amplification that contained 13 genes. FISH analysis demonstrated amplification of this region in 13.2% of high-grade ovarian carcinomas but not in any of low-grade carcinomas or benign ovarian tumors. Combined genetic and transcriptome analyses showed that Rsf-1 (HBXAPalpha) was the only gene that demonstrated consistent overexpression in all of the tumors harboring the 11q13.5 amplification. Patients with Rsf-1 amplification or overexpression had a significantly shorter overall survival than those without. Overexpression of Rsf-1 gene stimulated cell proliferation and transform nonneoplastic cells by conferring serum-independent and anchorage-independent growth. Furthermore, Rsf-1 gene knockdown inhibited cell growth in OVCAR3 cells, which harbor Rsf-1 amplification. Taken together, these findings indicate an important role of Rsf-1 amplification in ovarian cancer.

SUBMITTER: Shih IeM

PROVIDER: S-EPMC1236547 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma.

Shih Ie-Ming IeM Sheu Jim Jinn-Chyuan JJ Santillan Antonio A Nakayama Kentaro K Yen M Jim MJ Bristow Robert E RE Vang Russell R Parmigiani Giovanni G Kurman Robert J RJ Trope Claes G CG Davidson Ben B Wang Tian-Li TL

Proceedings of the National Academy of Sciences of the United States of America 20050919 39

A genomewide technology, digital karyotyping, was used to identify subchromosomal alterations in ovarian cancer. Amplification at 11q13.5 was found in three of seven ovarian carcinomas, and amplicon mapping delineated a 1.8-Mb core of amplification that contained 13 genes. FISH analysis demonstrated amplification of this region in 13.2% of high-grade ovarian carcinomas but not in any of low-grade carcinomas or benign ovarian tumors. Combined genetic and transcriptome analyses showed that Rsf-1 ( ...[more]

PMID: 16172393

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Project description:Background:Human epidermal growth factor receptor 2 (HER2) has tyrosine kinase activity and is a member of the epidermal growth factor receptor family. This initiates a variety of signal for pathways which leads to cell proliferation and tumourigenesis. In approximately 15-30% of breast cancers and 10-30% of gastric/gastroesophageal cancers, amplification or overexpression of HER2 occurs, and it serves as a prognostic and predictive biomarker. HER-2/neu is one of the most frequently studied molecular biological parameters in epithelial ovarian cancer (EOC), but its prognostic impact has not been fully assessed. The objective of the current study was firstly to analyse the presence of HER-2 overexpression in EOC patients and secondly to evaluate association between human epidermal growth factor receptor 2 (HER-2/neu) expression and progression-free survival in patients with EOC. Method:In this prospective study of 2 years in our department, 186 gynaecological cancers were operated out of which 98 cases were operated for epithelial ovarian cancer and rest for cervical cancer, endometrial cancer, and other subtypes of ovarian cancer. In this study, HER2 gene status was evaluated in EOC by immunohistochemistry analysis, and overall survival of these patients was evaluated. Results:HER-2 overexpression was found in 22 of the 98 investigated cases (22.45%), in which 14 OC (14.29%) were weakly positive and 8 OC (8.16%) were moderately to intensely positive. In the study, increased HER2 expression was associated with decreased progression-free survival (PFS) and hence poor prognosis (P 0.054). Conclusions:The introduction of HER2-directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers. The present study findings provided that HER-2/neu expression in patients with OC has an adverse impact on the PFS. Therefore, our results show that the decision algorithm usually used in breast cancer by HER2 may be appropriate in ovarian cancer.

Project description:BackgroundEpithelial ovarian cancer (EOC) is the most common cause of gynecological malignancy-related mortality. Ovarian clear cell carcinoma (CCC) has unique clinical characteristics and behaviors that differ from other histological types of EOC, including a frequent association with endometriosis and a highly chemoresistant nature, resulting in poor prognosis. However, factors underlying its malignant behavior are still poorly understood. Aberrant expression of microRNAs has been shown to be involved in oncogenesis, and microRNA-21 (miR-21) is frequently overexpressed in many types of cancers. The aim of this study was to investigate the role of miR-21 in 17q23-25 amplification associated with CCC oncogenesis.MethodsWe identified 17q23-25 copy number aberrations among 28 primary CCC tumors by using a comparative genomic hybridization method. Next, we measured expression levels of the candidate target genes, miR-21 and PPM1D, for 17q23-25 amplification by real-time RT-PCR analysis and compared those data with copy number status and clinicopathological features. In addition, immunohistochemical analysis of PTEN (a potential target of miR-21) was performed using the same primary CCC cases. We investigated the biological significance of miR-21 overexpression in CCC using a loss-of-function antisense approach.Results17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 CCC cases (14.2%). The patients with 17q23-25 amplification had significantly shorter progression-free and overall survival than those without 17q23-25 amplification (log-rank test: p = 0.0496; p = 0.0469, respectively). A significant correlation was observed between miR-21 overexpression and endometriosis. Both PTEN mRNA and PTEN protein expression were increased by miR-21 knockdown in CCC cells. We also confirmed that miR-21 directly bound to the 3'-untranslated region of PTEN mRNA using a dual-luciferase reporter assay.ConclusionsMiR-21 is a possible driver gene other than PPM1D for 17q23-25 amplification in CCC. Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through the regulation of the PTEN tumor suppressor gene.

Dataset Information

Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma.

Publications

Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma.

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