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Published in: Journal of Cancer Research and Clinical Oncology 2/2013

01-02-2013 | Original Paper

Systematic analysis and validation of differential gene expression in ovarian serous adenocarcinomas and normal ovary

Authors: Dirk Bauerschlag, Karen Bräutigam, Roland Moll, Jalid Sehouli, Alexander Mustea, Darius Salehin, Maryla Krajewska, John C. Reed, Nicolai Maass, Garret M. Hampton, Ivo Meinhold-Heerlein

Published in: Journal of Cancer Research and Clinical Oncology | Issue 2/2013

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Abstract

Purpose

Cancer of the ovary confers the worst prognosis among women with gynecological malignancies, primarily because most ovarian cancers are diagnosed at late stage. Hence, there is a substantial need to develop new diagnostic biomarkers to enable detection of ovarian cancer at earlier stages, which would confer better prognosis. In addition, the identification of druggable targets is of substantial interest to find new therapeutic strategies for ovarian cancer.

Methods

The expression of 22,500 genes in a series of 67 serous papillary carcinomas was compared with 9 crudely enriched normal ovarian tissue samples by RNA hybridization on oligonucleotide microarrays. Multiple genes with near-uniformly expression were elevated in carcinomas of varying grade and malignant potential, including several previously described genes (e.g., MUC-1, CD9, CD24, claudin 3, and mesothelin). We performed immunohistochemical staining with antibodies against several of the proteins encoded by differentially expressed genes in an independent cohort of 71 cases of paraffin-embedded ovarian cancer samples.

Results

We found striking differences in EpCAM (p < 0.005), CD9 (p < 0.001), MUC-1 (p < 0.001), and claudin 3 proteins (p < 0.001) but not for mesothelin (p > 0.05) using the Mann–Whitney U test.

Conclusions

Protein expression of a majority of the differentially expressed genes tested was found to be elevated in ovarian carcinomas and, as such, define potential new biomarkers or targets.
Literature
go back to reference Auersperg N (2011) The origin of ovarian carcinomas: a unifying hypothesis. Int J Gynecol Pathol 30(1):12–21PubMedCrossRef Auersperg N (2011) The origin of ovarian carcinomas: a unifying hypothesis. Int J Gynecol Pathol 30(1):12–21PubMedCrossRef
go back to reference Bast RC Jr (2003) Status of tumor markers in ovarian cancer screening. J Clin Oncol 21(10 Suppl):200s–205sPubMedCrossRef Bast RC Jr (2003) Status of tumor markers in ovarian cancer screening. J Clin Oncol 21(10 Suppl):200s–205sPubMedCrossRef
go back to reference Bauerschlag DO, Ammerpohl O et al (2011) Progression-free survival in ovarian cancer is reflected in epigenetic DNA methylation profiles. Oncology 80(1–2):12–20PubMedCrossRef Bauerschlag DO, Ammerpohl O et al (2011) Progression-free survival in ovarian cancer is reflected in epigenetic DNA methylation profiles. Oncology 80(1–2):12–20PubMedCrossRef
go back to reference Brakora KA, Lee H et al (2004) Utility of osteopontin as a biomarker in recurrent epithelial ovarian cancer. Gynecol Oncol 93(2):361–365PubMedCrossRef Brakora KA, Lee H et al (2004) Utility of osteopontin as a biomarker in recurrent epithelial ovarian cancer. Gynecol Oncol 93(2):361–365PubMedCrossRef
go back to reference Budiu RA, Mantia-Smaldone G et al (2011) Soluble MUC1 and serum MUC1-specific antibodies are potential prognostic biomarkers for platinum-resistant ovarian cancer. Cancer Immunol Immunother 60(7):975–984PubMedCrossRef Budiu RA, Mantia-Smaldone G et al (2011) Soluble MUC1 and serum MUC1-specific antibodies are potential prognostic biomarkers for platinum-resistant ovarian cancer. Cancer Immunol Immunother 60(7):975–984PubMedCrossRef
go back to reference Burges A, Wimberger P et al (2007) Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM × anti-CD3 antibody: a phase I/II study. Clin Cancer Res 13(13):3899–3905PubMedCrossRef Burges A, Wimberger P et al (2007) Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM × anti-CD3 antibody: a phase I/II study. Clin Cancer Res 13(13):3899–3905PubMedCrossRef
go back to reference Cristaudo A, Bonotti A et al (2011) Soluble markers for diagnosis of malignant pleural mesothelioma. Biomark Med 5(2):261–273PubMedCrossRef Cristaudo A, Bonotti A et al (2011) Soluble markers for diagnosis of malignant pleural mesothelioma. Biomark Med 5(2):261–273PubMedCrossRef
go back to reference Dong Y, Walsh MD et al (1997) Expression of MUC1 and MUC2 mucins in epithelial ovarian tumours. J Pathol 183(3):311–317PubMedCrossRef Dong Y, Walsh MD et al (1997) Expression of MUC1 and MUC2 mucins in epithelial ovarian tumours. J Pathol 183(3):311–317PubMedCrossRef
go back to reference El-Sahwi K, Bellone S et al (2010) Overexpression of EpCAM in uterine serous papillary carcinoma: implications for EpCAM-specific immunotherapy with human monoclonal antibody adecatumumab (MT201). Mol Cancer Ther 9(1):57–66PubMedCrossRef El-Sahwi K, Bellone S et al (2010) Overexpression of EpCAM in uterine serous papillary carcinoma: implications for EpCAM-specific immunotherapy with human monoclonal antibody adecatumumab (MT201). Mol Cancer Ther 9(1):57–66PubMedCrossRef
go back to reference Fekete T, Raso E et al (2012) Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples. Int J Cancer 131(1):95–105 Fekete T, Raso E et al (2012) Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples. Int J Cancer 131(1):95–105
go back to reference Fryer RM, Randall J et al (2002) Global analysis of gene expression: methods, interpretation, and pitfalls. Exp Nephrol 10(2):64–74PubMedCrossRef Fryer RM, Randall J et al (2002) Global analysis of gene expression: methods, interpretation, and pitfalls. Exp Nephrol 10(2):64–74PubMedCrossRef
go back to reference Hassan R, Cohen SJ et al (2010) Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res 16(24):6132–6138PubMedCrossRef Hassan R, Cohen SJ et al (2010) Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res 16(24):6132–6138PubMedCrossRef
go back to reference Havrilesky LJ, Sanders GD et al (2011) Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction. Cancer 117(3):545–553PubMedCrossRef Havrilesky LJ, Sanders GD et al (2011) Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction. Cancer 117(3):545–553PubMedCrossRef
go back to reference Heinzelmann-Schwarz VA, Gardiner-Garden M et al (2004) Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Clin Cancer Res 10(13):4427–4436PubMedCrossRef Heinzelmann-Schwarz VA, Gardiner-Garden M et al (2004) Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Clin Cancer Res 10(13):4427–4436PubMedCrossRef
go back to reference Hellstrom I, Raycraft J et al (2003) The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res 63(13):3695–3700PubMed Hellstrom I, Raycraft J et al (2003) The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res 63(13):3695–3700PubMed
go back to reference Hong S, Dong H et al (2011) Gene co-expression network and functional module analysis of ovarian cancer. Int J Comput Biol Drug Des 4(2):147–164PubMedCrossRef Hong S, Dong H et al (2011) Gene co-expression network and functional module analysis of ovarian cancer. Int J Comput Biol Drug Des 4(2):147–164PubMedCrossRef
go back to reference Houle CD, Ding XY et al (2002) Loss of expression and altered localization of KAI1 and CD9 protein are associated with epithelial ovarian cancer progression. Gynecol Oncol 86(1):69–78PubMedCrossRef Houle CD, Ding XY et al (2002) Loss of expression and altered localization of KAI1 and CD9 protein are associated with epithelial ovarian cancer progression. Gynecol Oncol 86(1):69–78PubMedCrossRef
go back to reference Hwang JR, Jo K et al (2012) Upregulation of CD9 in ovarian cancer is related to the induction of TNF-alpha gene expression and constitutive NF-kappaB activation. Carcinogenesis 33(1):77–83PubMedCrossRef Hwang JR, Jo K et al (2012) Upregulation of CD9 in ovarian cancer is related to the induction of TNF-alpha gene expression and constitutive NF-kappaB activation. Carcinogenesis 33(1):77–83PubMedCrossRef
go back to reference Jager M, Schoberth A et al (2012) Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). Cancer Res 72(1):24–32PubMedCrossRef Jager M, Schoberth A et al (2012) Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). Cancer Res 72(1):24–32PubMedCrossRef
go back to reference Kim JH, Herlyn D et al (2003) Identification of epithelial cell adhesion molecule autoantibody in patients with ovarian cancer. Clin Cancer Res 9(13):4782–4791PubMed Kim JH, Herlyn D et al (2003) Identification of epithelial cell adhesion molecule autoantibody in patients with ovarian cancer. Clin Cancer Res 9(13):4782–4791PubMed
go back to reference King HC, Sinha AA (2001) Gene expression profile analysis by DNA microarrays: promise and pitfalls. JAMA 286(18):2280–2288PubMedCrossRef King HC, Sinha AA (2001) Gene expression profile analysis by DNA microarrays: promise and pitfalls. JAMA 286(18):2280–2288PubMedCrossRef
go back to reference Konstantinopoulos PA, Spentzos D et al (2008) Gene-expression profiling in epithelial ovarian cancer. Nat Clin Pract Oncol 5(10):577–587PubMedCrossRef Konstantinopoulos PA, Spentzos D et al (2008) Gene-expression profiling in epithelial ovarian cancer. Nat Clin Pract Oncol 5(10):577–587PubMedCrossRef
go back to reference Krajewski S, Bodrug S et al (1994) Immunohistochemical analysis of Mcl-1 and Bcl-2 proteins in normal and neoplastic lymph nodes. Am J Pathol 145(3):515–525PubMed Krajewski S, Bodrug S et al (1994) Immunohistochemical analysis of Mcl-1 and Bcl-2 proteins in normal and neoplastic lymph nodes. Am J Pathol 145(3):515–525PubMed
go back to reference Krajewski S, Krajewska M et al (1999) Prognostic significance of apoptosis regulators in breast cancer. Endocr Relat Cancer 6(1):29–40PubMedCrossRef Krajewski S, Krajewska M et al (1999) Prognostic significance of apoptosis regulators in breast cancer. Endocr Relat Cancer 6(1):29–40PubMedCrossRef
go back to reference Kurman RJ, Shih Ie M (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34(3):433–443PubMedCrossRef Kurman RJ, Shih Ie M (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34(3):433–443PubMedCrossRef
go back to reference Kurman RJ, Shih Ie M (2011) Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Hum Pathol 42(7):918–931PubMedCrossRef Kurman RJ, Shih Ie M (2011) Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Hum Pathol 42(7):918–931PubMedCrossRef
go back to reference Lockhart DJ, Dong H et al (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14(13):1675–1680PubMedCrossRef Lockhart DJ, Dong H et al (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14(13):1675–1680PubMedCrossRef
go back to reference Meinhold-Heerlein I, Stenner-Liewen F et al (2001) Expression and potential role of Fas-associated phosphatase-1 in ovarian cancer. Am J Pathol 158(4):1335–1344PubMedCrossRef Meinhold-Heerlein I, Stenner-Liewen F et al (2001) Expression and potential role of Fas-associated phosphatase-1 in ovarian cancer. Am J Pathol 158(4):1335–1344PubMedCrossRef
go back to reference Meinhold-Heerlein I, Bauerschlag D et al (2005) Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene 24(6):1053–1065PubMedCrossRef Meinhold-Heerlein I, Bauerschlag D et al (2005) Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene 24(6):1053–1065PubMedCrossRef
go back to reference Meinhold-Heerlein I, Bauerschlag D et al (2007) An integrated clinical-genomics approach identifies a candidate multi-analyte blood test for serous ovarian carcinoma. Clin Cancer Res 13(2 Pt 1):458–466PubMedCrossRef Meinhold-Heerlein I, Bauerschlag D et al (2007) An integrated clinical-genomics approach identifies a candidate multi-analyte blood test for serous ovarian carcinoma. Clin Cancer Res 13(2 Pt 1):458–466PubMedCrossRef
go back to reference Mok SC, Chao J et al (2001) Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology. J Natl Cancer Inst 93(19):1458–1464PubMedCrossRef Mok SC, Chao J et al (2001) Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology. J Natl Cancer Inst 93(19):1458–1464PubMedCrossRef
go back to reference Mor G, Visintin I et al (2005) Serum protein markers for early detection of ovarian cancer. Proc Natl Acad Sci USA 102(21):7677–7682PubMedCrossRef Mor G, Visintin I et al (2005) Serum protein markers for early detection of ovarian cancer. Proc Natl Acad Sci USA 102(21):7677–7682PubMedCrossRef
go back to reference Ott MG, Marme F et al (2012) Humoral response to catumaxomab correlates with clinical outcome: results of the pivotal phase II/III study in patients with malignant ascites. Int J Cancer 130(9):2195–2203 Ott MG, Marme F et al (2012) Humoral response to catumaxomab correlates with clinical outcome: results of the pivotal phase II/III study in patients with malignant ascites. Int J Cancer 130(9):2195–2203
go back to reference Ralhan R, Cao J et al (2010) EpCAM nuclear localization identifies aggressive thyroid cancer and is a marker for poor prognosis. BMC Cancer 10:331PubMedCrossRef Ralhan R, Cao J et al (2010) EpCAM nuclear localization identifies aggressive thyroid cancer and is a marker for poor prognosis. BMC Cancer 10:331PubMedCrossRef
go back to reference Rangel LB, Agarwal R et al (2003) Tight junction proteins claudin-3 and claudin-4 are frequently over-expressed in ovarian cancer but not in ovarian cystadenomas. Clin Cancer Res 9(7):2567–2575PubMed Rangel LB, Agarwal R et al (2003) Tight junction proteins claudin-3 and claudin-4 are frequently over-expressed in ovarian cancer but not in ovarian cystadenomas. Clin Cancer Res 9(7):2567–2575PubMed
go back to reference Rentrop M, Knapp B et al (1986) Aminoalkylsilane-treated glass slides as support for in situ hybridization of keratin cDNAs to frozen tissue sections under varying fixation and pretreatment conditions. Histochem J 18(5):271–276PubMedCrossRef Rentrop M, Knapp B et al (1986) Aminoalkylsilane-treated glass slides as support for in situ hybridization of keratin cDNAs to frozen tissue sections under varying fixation and pretreatment conditions. Histochem J 18(5):271–276PubMedCrossRef
go back to reference Schummer M, Drescher C et al (2012) Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125. Gynecol Oncol 125(1):65–69 Schummer M, Drescher C et al (2012) Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125. Gynecol Oncol 125(1):65–69
go back to reference Spellman PT, Bell D et al (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474(7353):609–615CrossRef Spellman PT, Bell D et al (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474(7353):609–615CrossRef
go back to reference Spizzo G, Went P et al (2004) High Ep-CAM expression is associated with poor prognosis in node-positive breast cancer. Breast Cancer Res Treat 86(3):207–213PubMedCrossRef Spizzo G, Went P et al (2004) High Ep-CAM expression is associated with poor prognosis in node-positive breast cancer. Breast Cancer Res Treat 86(3):207–213PubMedCrossRef
go back to reference Spizzo G, Fong D et al (2011) EpCAM expression in primary tumour tissues and metastases: an immunohistochemical analysis. J Clin Pathol 64(5):415–420PubMedCrossRef Spizzo G, Fong D et al (2011) EpCAM expression in primary tumour tissues and metastases: an immunohistochemical analysis. J Clin Pathol 64(5):415–420PubMedCrossRef
go back to reference Sun C, Yi T et al (2011) Efficient inhibition of ovarian cancer by short hairpin RNA targeting claudin-3. Oncol Rep 26(1):193–200PubMed Sun C, Yi T et al (2011) Efficient inhibition of ovarian cancer by short hairpin RNA targeting claudin-3. Oncol Rep 26(1):193–200PubMed
go back to reference Taylor JM, Ankerst DP et al (2008) Validation of biomarker-based risk prediction models. Clin Cancer Res 14(19):5977–5983PubMedCrossRef Taylor JM, Ankerst DP et al (2008) Validation of biomarker-based risk prediction models. Clin Cancer Res 14(19):5977–5983PubMedCrossRef
go back to reference Van Elssen CH, Frings PW et al (2010) Expression of aberrantly glycosylated Mucin-1 in ovarian cancer. Histopathology 57(4):597–606PubMedCrossRef Van Elssen CH, Frings PW et al (2010) Expression of aberrantly glycosylated Mucin-1 in ovarian cancer. Histopathology 57(4):597–606PubMedCrossRef
go back to reference Wang L, Ma J et al (2007) Expression of MUC1 in primary and metastatic human epithelial ovarian cancer and its therapeutic significance. Gynecol Oncol 105(3):695–702PubMedCrossRef Wang L, Ma J et al (2007) Expression of MUC1 in primary and metastatic human epithelial ovarian cancer and its therapeutic significance. Gynecol Oncol 105(3):695–702PubMedCrossRef
go back to reference Welsh JB, Sapinoso LM et al (2001a) Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 61(16):5974–5978PubMed Welsh JB, Sapinoso LM et al (2001a) Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 61(16):5974–5978PubMed
go back to reference Welsh JB, Zarrinkar PP et al (2001b) Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci USA 98(3):1176–1181PubMedCrossRef Welsh JB, Zarrinkar PP et al (2001b) Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci USA 98(3):1176–1181PubMedCrossRef
go back to reference Wodicka L, Dong H et al (1997) Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat Biotechnol 15(13):1359–1367PubMedCrossRef Wodicka L, Dong H et al (1997) Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat Biotechnol 15(13):1359–1367PubMedCrossRef
go back to reference Yen MJ, Hsu CY et al (2006) Diffuse mesothelin expression correlates with prolonged patient survival in ovarian serous carcinoma. Clin Cancer Res 12(3 Pt 1):827–831PubMedCrossRef Yen MJ, Hsu CY et al (2006) Diffuse mesothelin expression correlates with prolonged patient survival in ovarian serous carcinoma. Clin Cancer Res 12(3 Pt 1):827–831PubMedCrossRef
Metadata
Title
Systematic analysis and validation of differential gene expression in ovarian serous adenocarcinomas and normal ovary
Authors
Dirk Bauerschlag
Karen Bräutigam
Roland Moll
Jalid Sehouli
Alexander Mustea
Darius Salehin
Maryla Krajewska
John C. Reed
Nicolai Maass
Garret M. Hampton
Ivo Meinhold-Heerlein
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 2/2013
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-012-1334-8

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