Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human LMP ovarian tumors and low-grade ovarian carcinomas to identify genes which dffer from high-grade ovarian carcinomas - PAX2: a potential biomarker for low malignant potential ovarian tumors and low-grade serous ovarian carcinomas

ABSTRACT: Objective: Ovarian tumors of low-malignant potential (LMP) and low-grade serous ovarian carcinomas are thought to represent different stages on a tumorigenic continuum and to develop along pathways distinct from that of high-grade serous ovarian carcinoma. Past studies have utilized gene expression profiles to support this theory. The objective of the current study was to identify new genes whose expression profiles in LMP ovarian tumors and low-grade ovarian carcinomas differ from that in high-grade ovarian carcinomas. Methods: We used RNA from 3 normal human ovarian surface epithelia (HOSE) and from 10 low-grade and 10 high-grade serous ovarian carcinoma samples to perform gene expression profiling. Using real-time reverse-transcription polymerase chain reaction (RT-PCR), we evaluated changes in PAX2 mRNA expression in cDNA created from RNA extracted from an independent set of ovarian tissue samples (7 LMP tumors and 17 low-grade and 23 high-grade serous carcinomas). We also examined PAX2 expression using Western blot analysis of protein extracted from a set of ovarian LMP and low- and high-grade carcinoma tissue samples. Additionally, we used immunohistochemistry (IHC) to validate PAX2 overexpression in a third independent set of paraffin ovarian tissue sections from 17 LMP tumors and 16 low- and 257 high-grade carcinomas. Results: Gene profiling revealed higher expression of PAX2 in low-grade than in high-grade ovarian carcinomas. Real-time RT-PCR demonstrated a statistically significant difference in median PAX2 mRNA expression, expressed as fold change, among ovarian LMP tumor (1837.38), low-grade (183.12), and high-grade (3.72) carcinoma samples (p=0.015). Western blot analysis revealed strong PAX2 expression in ovarian LMP and low-grade carcinoma samples but no PAX2 protein expression in high-grade carcinomas. On IHC, more LMP tumor and low-grade carcinoma samples expressed moderate to high levels of PAX2 than did high-grade ovarian carcinoma samples. The numbers of samples with strong nuclear staining was significantly higher for ovarian LMP tumors (10 of 17, p<0.001) and low-grade serous carcinomas (10 of 16, p<0.001) than for high-grade carcinomas (27 of 257). Discussion: Our identification and validation of higher PAX2 expression in ovarian LMP tumors and low-grade serous carcinomas than in high-grade carcinomas supports the two-tiered hypothesis that the first two are on a continuum and are distinct from high-grade ovarian carcinomas. PAX2 may represent a potential biomarker and future therapeutic target for individualizing chemotherapy for ovarian LMP tumors and low-grade carcinomas in the future. Experiment Overall Design: We used RNA from 3 normal human ovarian surface epithelia (HOSE) and from 10 low-grade and 10 high-grade serous ovarian carcinoma samples to perform gene expression profiling. Using real-time reverse-transcription polymerase chain reaction (RT-PCR), we evaluated changes in PAX2 mRNA expression in cDNA created from RNA extracted from an independent set of ovarian tissue samples (7 LMP tumors and 17 low-grade and 23 high-grade serous carcinomas). We also examined PAX2 expression using Western blot analysis of protein extracted from a set of ovarian LMP and low- and high-grade carcinoma tissue samples. Additionally, we used immunohistochemistry (IHC) to validate PAX2 overexpression in a third independent set of paraffin ovarian tissue sections from 17 LMP tumors and 16 low- and 257 high-grade carcinomas.

ORGANISM(S): Homo sapiens

SUBMITTER: Kwong-Kwok Wong

PROVIDER: E-GEOD-14001 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

PAX2 expression in low malignant potential ovarian tumors and low-grade ovarian serous carcinomas.

Tung Celestine S CS Mok Samuel C SC Tsang Yvonne T M YT Zu Zhifei Z Song Huijuan H Liu Jinsong J Deavers Michael T MT Malpica Anais A Wolf Judith K JK Lu Karen H KH Gershenson David M DM Wong Kwong-Kwok KK

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20090612 9

Ovarian tumors of low malignant potential and low-grade ovarian serous carcinomas are thought to represent different stages on a tumorigenic continuum and to develop along pathways distinct from high-grade ovarian serous carcinoma. We performed gene expression profiling on three normal human ovarian surface epithelia samples, and 10 low-grade and 10 high-grade ovarian serous carcinomas. Analysis of gene expression profiles of these samples has identified 80 genes upregulated and 232 genes downre ...[more]

PMID: 19525924

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Project description:Objective: Ovarian tumors of low-malignant potential (LMP) and low-grade serous ovarian carcinomas are thought to represent different stages on a tumorigenic continuum and to develop along pathways distinct from that of high-grade serous ovarian carcinoma. Past studies have utilized gene expression profiles to support this theory. The objective of the current study was to identify new genes whose expression profiles in LMP ovarian tumors and low-grade ovarian carcinomas differ from that in high-grade ovarian carcinomas. Methods: We used RNA from 3 normal human ovarian surface epithelia (HOSE) and from 10 low-grade and 10 high-grade serous ovarian carcinoma samples to perform gene expression profiling. Using real-time reverse-transcription polymerase chain reaction (RT-PCR), we evaluated changes in PAX2 mRNA expression in cDNA created from RNA extracted from an independent set of ovarian tissue samples (7 LMP tumors and 17 low-grade and 23 high-grade serous carcinomas). We also examined PAX2 expression using Western blot analysis of protein extracted from a set of ovarian LMP and low- and high-grade carcinoma tissue samples. Additionally, we used immunohistochemistry (IHC) to validate PAX2 overexpression in a third independent set of paraffin ovarian tissue sections from 17 LMP tumors and 16 low- and 257 high-grade carcinomas. Results: Gene profiling revealed higher expression of PAX2 in low-grade than in high-grade ovarian carcinomas. Real-time RT-PCR demonstrated a statistically significant difference in median PAX2 mRNA expression, expressed as fold change, among ovarian LMP tumor (1837.38), low-grade (183.12), and high-grade (3.72) carcinoma samples (p=0.015). Western blot analysis revealed strong PAX2 expression in ovarian LMP and low-grade carcinoma samples but no PAX2 protein expression in high-grade carcinomas. On IHC, more LMP tumor and low-grade carcinoma samples expressed moderate to high levels of PAX2 than did high-grade ovarian carcinoma samples. The numbers of samples with strong nuclear staining was significantly higher for ovarian LMP tumors (10 of 17, p<0.001) and low-grade serous carcinomas (10 of 16, p<0.001) than for high-grade carcinomas (27 of 257). Discussion: Our identification and validation of higher PAX2 expression in ovarian LMP tumors and low-grade serous carcinomas than in high-grade carcinomas supports the two-tiered hypothesis that the first two are on a continuum and are distinct from high-grade ovarian carcinomas. PAX2 may represent a potential biomarker and future therapeutic target for individualizing chemotherapy for ovarian LMP tumors and low-grade carcinomas in the future.

Project description:Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 22 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas. Total RNA were extracted from microdissected human ovarian surface epithelia (HOSE, n=6), and microdissected serous borderline ovarian tumors (LMP, n=8), low-grade serous ovarian carcinomas (LGOSC, n=13), and 22 high-grade serous ovarian carcinomas (HGOSC, n=22). Gene Expression profiles were then generated with commercial GeneChip Human Genome U133 Plus 2.0 Array. dChip was used to identify significant differentially expressed genes between LMP/LGOSC and HGOSC

Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed.

Dataset Information

Transcription profiling of human LMP ovarian tumors and low-grade ovarian carcinomas to identify genes which dffer from high-grade ovarian carcinomas - PAX2: a potential biomarker for low malignant potential ovarian tumors and low-grade serous ovarian carcinomas

Publications

PAX2 expression in low malignant potential ovarian tumors and low-grade ovarian serous carcinomas.

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