Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis

Karen H. Lu, Andrea P. Patterson, Lin Wang, Rebecca T. Marquez, Edward N. Atkinson, Keith A. Baggerly, Lance R. Ramoth, Daniel G. Rosen, Jinsong Liu, Ingegerd Hellstrom, David Smith, Lynn Hartmann, David Fishman, Andrew Berchuck, Rosemarie Schmandt, Regina Whitaker, David M. Gershenson, Gordon Mills, Robert C. Bast

Research output: Contribution to journalArticle

319 Citations (Scopus)

Abstract

Purpose: Advanced-stage epithelial ovarian cancer has a poor prognosis with long-term survival in less than 30% of patients. When the disease is detected in stage I, more than 90% of patients can be cured by conventional therapy. Screening for early-stage disease with individual serum tumor markers, such as CA125, is limited by the fact that no single marker is up-regulated and shed in adequate amounts by all ovarian cancers. Consequently, use of multiple markers in combination might detect a larger fraction of early-stage ovarian cancers. Experimental Design: To identify potential candidates for novel markers, we have used Affymetrix human genome arrays (U95 series) to analyze differences in gene expression of 41,441 known genes and expressed sequence tags between five pools of normal ovarian surface epithelial cells (OSE) and 42 epithelial ovarian cancers of different stages, grades, and histotypes. Recursive descent partition analysis (RDPA) was performed with 102 probe sets representing 86 genes that were up-regulated at least 3-fold in epithelial ovarian cancers when compared with normal OSE. In addition, a panel of 11 genes known to encode potential tumor markers [mucin 1, transmembrane (MUC1), mucin 16 (CA125), mesothelin, WAP four-disulfide core domain 2 (HE4), kallikrein 6, kallikrein 10, matrix metalloproteinase 2, prostasin, osteopontin, tetranectin, and inhibin] were similarly analyzed. Results: The 3-fold up-regulated genes were examined and four genes [Notch homologue 3 (NOTCH3), E2F transcription factor 3 (E2F3), GTPase activating protein (RAC-GAP1), and hematological and neurological expressed 1 (HN1)] distinguished all tumor samples from normal OSE. The 3-fold up-regulated genes were analyzed using RDPA, and the combination of elevated claudin 3 (CLDN3) and elevated vascular endothelial growth factor (VEGF) distinguished the cancers from normal OSE. The 11 known markers were analyzed using RDPA, and a combination of HE4, CA125, and MUC1 expression could distinguish tumor from normal specimens. Expression at the mRNA level in the candidate markers was examined via semiquantitative reverse transcription-PCR and was found to correlate well with the array data. Immunohistochemistry was performed to identify expression of the genes at the protein level in 158 ovarian cancers of different histotypes. A combination of CLDN3, CA125, and MUC1 stained 157 (99.4%) of 158 cancers, and all of the tumors were detected with a combination of CLDN3, CA125, MUC1, and VEGF. Conclusions: Our data are consistent with the possibility that a limited number of markers in combination might identify >99% of epithelial ovarian cancers despite the heterogeneity of the disease.

Original languageEnglish (US)
Pages (from-to)3291-3300
Number of pages10
JournalClinical Cancer Research
Volume10
Issue number10
DOIs
StatePublished - May 15 2004
Externally publishedYes

Fingerprint

Neoplasm Genes
Mucin-1
Claudin-3
Gene Expression
Ovarian Neoplasms
Epithelial Cells
Genes
Tumor Biomarkers
E2F3 Transcription Factor
Vascular Endothelial Growth Factor A
Neoplasms
CA-125 Antigen
GTPase-Activating Proteins
Tissue Kallikreins
Inhibins
Osteopontin
Kallikreins
Matrix Metalloproteinase 2
Expressed Sequence Tags
Human Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lu, K. H., Patterson, A. P., Wang, L., Marquez, R. T., Atkinson, E. N., Baggerly, K. A., ... Bast, R. C. (2004). Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clinical Cancer Research, 10(10), 3291-3300. https://doi.org/10.1158/1078-0432.CCR-03-0409

Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. / Lu, Karen H.; Patterson, Andrea P.; Wang, Lin; Marquez, Rebecca T.; Atkinson, Edward N.; Baggerly, Keith A.; Ramoth, Lance R.; Rosen, Daniel G.; Liu, Jinsong; Hellstrom, Ingegerd; Smith, David; Hartmann, Lynn; Fishman, David; Berchuck, Andrew; Schmandt, Rosemarie; Whitaker, Regina; Gershenson, David M.; Mills, Gordon; Bast, Robert C.

In: Clinical Cancer Research, Vol. 10, No. 10, 15.05.2004, p. 3291-3300.

Research output: Contribution to journalArticle

Lu, KH, Patterson, AP, Wang, L, Marquez, RT, Atkinson, EN, Baggerly, KA, Ramoth, LR, Rosen, DG, Liu, J, Hellstrom, I, Smith, D, Hartmann, L, Fishman, D, Berchuck, A, Schmandt, R, Whitaker, R, Gershenson, DM, Mills, G & Bast, RC 2004, 'Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis', Clinical Cancer Research, vol. 10, no. 10, pp. 3291-3300. https://doi.org/10.1158/1078-0432.CCR-03-0409
Lu, Karen H. ; Patterson, Andrea P. ; Wang, Lin ; Marquez, Rebecca T. ; Atkinson, Edward N. ; Baggerly, Keith A. ; Ramoth, Lance R. ; Rosen, Daniel G. ; Liu, Jinsong ; Hellstrom, Ingegerd ; Smith, David ; Hartmann, Lynn ; Fishman, David ; Berchuck, Andrew ; Schmandt, Rosemarie ; Whitaker, Regina ; Gershenson, David M. ; Mills, Gordon ; Bast, Robert C. / Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 10. pp. 3291-3300.
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title = "Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis",
abstract = "Purpose: Advanced-stage epithelial ovarian cancer has a poor prognosis with long-term survival in less than 30{\%} of patients. When the disease is detected in stage I, more than 90{\%} of patients can be cured by conventional therapy. Screening for early-stage disease with individual serum tumor markers, such as CA125, is limited by the fact that no single marker is up-regulated and shed in adequate amounts by all ovarian cancers. Consequently, use of multiple markers in combination might detect a larger fraction of early-stage ovarian cancers. Experimental Design: To identify potential candidates for novel markers, we have used Affymetrix human genome arrays (U95 series) to analyze differences in gene expression of 41,441 known genes and expressed sequence tags between five pools of normal ovarian surface epithelial cells (OSE) and 42 epithelial ovarian cancers of different stages, grades, and histotypes. Recursive descent partition analysis (RDPA) was performed with 102 probe sets representing 86 genes that were up-regulated at least 3-fold in epithelial ovarian cancers when compared with normal OSE. In addition, a panel of 11 genes known to encode potential tumor markers [mucin 1, transmembrane (MUC1), mucin 16 (CA125), mesothelin, WAP four-disulfide core domain 2 (HE4), kallikrein 6, kallikrein 10, matrix metalloproteinase 2, prostasin, osteopontin, tetranectin, and inhibin] were similarly analyzed. Results: The 3-fold up-regulated genes were examined and four genes [Notch homologue 3 (NOTCH3), E2F transcription factor 3 (E2F3), GTPase activating protein (RAC-GAP1), and hematological and neurological expressed 1 (HN1)] distinguished all tumor samples from normal OSE. The 3-fold up-regulated genes were analyzed using RDPA, and the combination of elevated claudin 3 (CLDN3) and elevated vascular endothelial growth factor (VEGF) distinguished the cancers from normal OSE. The 11 known markers were analyzed using RDPA, and a combination of HE4, CA125, and MUC1 expression could distinguish tumor from normal specimens. Expression at the mRNA level in the candidate markers was examined via semiquantitative reverse transcription-PCR and was found to correlate well with the array data. Immunohistochemistry was performed to identify expression of the genes at the protein level in 158 ovarian cancers of different histotypes. A combination of CLDN3, CA125, and MUC1 stained 157 (99.4{\%}) of 158 cancers, and all of the tumors were detected with a combination of CLDN3, CA125, MUC1, and VEGF. Conclusions: Our data are consistent with the possibility that a limited number of markers in combination might identify >99{\%} of epithelial ovarian cancers despite the heterogeneity of the disease.",
author = "Lu, {Karen H.} and Patterson, {Andrea P.} and Lin Wang and Marquez, {Rebecca T.} and Atkinson, {Edward N.} and Baggerly, {Keith A.} and Ramoth, {Lance R.} and Rosen, {Daniel G.} and Jinsong Liu and Ingegerd Hellstrom and David Smith and Lynn Hartmann and David Fishman and Andrew Berchuck and Rosemarie Schmandt and Regina Whitaker and Gershenson, {David M.} and Gordon Mills and Bast, {Robert C.}",
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T1 - Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis

AU - Lu, Karen H.

AU - Patterson, Andrea P.

AU - Wang, Lin

AU - Marquez, Rebecca T.

AU - Atkinson, Edward N.

AU - Baggerly, Keith A.

AU - Ramoth, Lance R.

AU - Rosen, Daniel G.

AU - Liu, Jinsong

AU - Hellstrom, Ingegerd

AU - Smith, David

AU - Hartmann, Lynn

AU - Fishman, David

AU - Berchuck, Andrew

AU - Schmandt, Rosemarie

AU - Whitaker, Regina

AU - Gershenson, David M.

AU - Mills, Gordon

AU - Bast, Robert C.

PY - 2004/5/15

Y1 - 2004/5/15

N2 - Purpose: Advanced-stage epithelial ovarian cancer has a poor prognosis with long-term survival in less than 30% of patients. When the disease is detected in stage I, more than 90% of patients can be cured by conventional therapy. Screening for early-stage disease with individual serum tumor markers, such as CA125, is limited by the fact that no single marker is up-regulated and shed in adequate amounts by all ovarian cancers. Consequently, use of multiple markers in combination might detect a larger fraction of early-stage ovarian cancers. Experimental Design: To identify potential candidates for novel markers, we have used Affymetrix human genome arrays (U95 series) to analyze differences in gene expression of 41,441 known genes and expressed sequence tags between five pools of normal ovarian surface epithelial cells (OSE) and 42 epithelial ovarian cancers of different stages, grades, and histotypes. Recursive descent partition analysis (RDPA) was performed with 102 probe sets representing 86 genes that were up-regulated at least 3-fold in epithelial ovarian cancers when compared with normal OSE. In addition, a panel of 11 genes known to encode potential tumor markers [mucin 1, transmembrane (MUC1), mucin 16 (CA125), mesothelin, WAP four-disulfide core domain 2 (HE4), kallikrein 6, kallikrein 10, matrix metalloproteinase 2, prostasin, osteopontin, tetranectin, and inhibin] were similarly analyzed. Results: The 3-fold up-regulated genes were examined and four genes [Notch homologue 3 (NOTCH3), E2F transcription factor 3 (E2F3), GTPase activating protein (RAC-GAP1), and hematological and neurological expressed 1 (HN1)] distinguished all tumor samples from normal OSE. The 3-fold up-regulated genes were analyzed using RDPA, and the combination of elevated claudin 3 (CLDN3) and elevated vascular endothelial growth factor (VEGF) distinguished the cancers from normal OSE. The 11 known markers were analyzed using RDPA, and a combination of HE4, CA125, and MUC1 expression could distinguish tumor from normal specimens. Expression at the mRNA level in the candidate markers was examined via semiquantitative reverse transcription-PCR and was found to correlate well with the array data. Immunohistochemistry was performed to identify expression of the genes at the protein level in 158 ovarian cancers of different histotypes. A combination of CLDN3, CA125, and MUC1 stained 157 (99.4%) of 158 cancers, and all of the tumors were detected with a combination of CLDN3, CA125, MUC1, and VEGF. Conclusions: Our data are consistent with the possibility that a limited number of markers in combination might identify >99% of epithelial ovarian cancers despite the heterogeneity of the disease.

AB - Purpose: Advanced-stage epithelial ovarian cancer has a poor prognosis with long-term survival in less than 30% of patients. When the disease is detected in stage I, more than 90% of patients can be cured by conventional therapy. Screening for early-stage disease with individual serum tumor markers, such as CA125, is limited by the fact that no single marker is up-regulated and shed in adequate amounts by all ovarian cancers. Consequently, use of multiple markers in combination might detect a larger fraction of early-stage ovarian cancers. Experimental Design: To identify potential candidates for novel markers, we have used Affymetrix human genome arrays (U95 series) to analyze differences in gene expression of 41,441 known genes and expressed sequence tags between five pools of normal ovarian surface epithelial cells (OSE) and 42 epithelial ovarian cancers of different stages, grades, and histotypes. Recursive descent partition analysis (RDPA) was performed with 102 probe sets representing 86 genes that were up-regulated at least 3-fold in epithelial ovarian cancers when compared with normal OSE. In addition, a panel of 11 genes known to encode potential tumor markers [mucin 1, transmembrane (MUC1), mucin 16 (CA125), mesothelin, WAP four-disulfide core domain 2 (HE4), kallikrein 6, kallikrein 10, matrix metalloproteinase 2, prostasin, osteopontin, tetranectin, and inhibin] were similarly analyzed. Results: The 3-fold up-regulated genes were examined and four genes [Notch homologue 3 (NOTCH3), E2F transcription factor 3 (E2F3), GTPase activating protein (RAC-GAP1), and hematological and neurological expressed 1 (HN1)] distinguished all tumor samples from normal OSE. The 3-fold up-regulated genes were analyzed using RDPA, and the combination of elevated claudin 3 (CLDN3) and elevated vascular endothelial growth factor (VEGF) distinguished the cancers from normal OSE. The 11 known markers were analyzed using RDPA, and a combination of HE4, CA125, and MUC1 expression could distinguish tumor from normal specimens. Expression at the mRNA level in the candidate markers was examined via semiquantitative reverse transcription-PCR and was found to correlate well with the array data. Immunohistochemistry was performed to identify expression of the genes at the protein level in 158 ovarian cancers of different histotypes. A combination of CLDN3, CA125, and MUC1 stained 157 (99.4%) of 158 cancers, and all of the tumors were detected with a combination of CLDN3, CA125, MUC1, and VEGF. Conclusions: Our data are consistent with the possibility that a limited number of markers in combination might identify >99% of epithelial ovarian cancers despite the heterogeneity of the disease.

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