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Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Comparative survival analysis of breast cancer microarray studies identifies important prognostic genetic pathways

Authors: Jeffrey C Miecznikowski, Dan Wang, Song Liu, Lara Sucheston, David Gold

Published in: BMC Cancer | Issue 1/2010

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Abstract

Background

An estimated 12% of females in the United States will develop breast cancer in their lifetime. Although, there are advances in treatment options including surgery and chemotherapy, breast cancer is still the second most lethal cancer in women. Thus, there is a clear need for better methods to predict prognosis for each breast cancer patient. With the advent of large genetic databases and the reduction in cost for the experiments, researchers are faced with choosing from a large pool of potential prognostic markers from numerous breast cancer gene expression profile studies.

Methods

Five microarray datasets related to breast cancer were examined using gene set analysis and the cancers were categorized into different subtypes using a scoring system based on genetic pathway activity.

Results

We have observed that significant genes in the individual studies show little reproducibility across the datasets. From our comparative analysis, using gene pathways with clinical variables is more reliable across studies and shows promise in assessing a patient's prognosis.

Conclusions

This study concludes that, in light of clinical variables, there are significant gene pathways in common across the datasets. Specifically, several pathways can further significantly stratify patients for survival. These candidate pathways should help to develop a panel of significant biomarkers for the prognosis of breast cancer patients in a clinical setting.
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Literature
2.
go back to reference Gao X, Nawaz Z: Progesterone receptors- animal models and cell signaling in breast cancer: Role of steroid receptor coactivators and corepressors of progesterone receptors in breast cancer. Breast Cancer Res. 2002, 4 (5): 182-10.1186/bcr449.CrossRefPubMedPubMedCentral Gao X, Nawaz Z: Progesterone receptors- animal models and cell signaling in breast cancer: Role of steroid receptor coactivators and corepressors of progesterone receptors in breast cancer. Breast Cancer Res. 2002, 4 (5): 182-10.1186/bcr449.CrossRefPubMedPubMedCentral
3.
go back to reference Hynes N, Stern D: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochimica et biophysica acta. 1994, 1198 (2-3): 165-PubMed Hynes N, Stern D: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochimica et biophysica acta. 1994, 1198 (2-3): 165-PubMed
4.
go back to reference Koumoundourou D, Kassimatis T, Zolota V, Tzorakoeleftherakis E, Ravazoula P, Vassiliou V, Kardamakis D, Varakis J: Prognostic Significance of TGFβ-1 and pSmad2/3 in Breast Cancer Patients with T1-2, N0 Tumours. Anticancer research. 2007, 27 (4C): 2613-PubMed Koumoundourou D, Kassimatis T, Zolota V, Tzorakoeleftherakis E, Ravazoula P, Vassiliou V, Kardamakis D, Varakis J: Prognostic Significance of TGFβ-1 and pSmad2/3 in Breast Cancer Patients with T1-2, N0 Tumours. Anticancer research. 2007, 27 (4C): 2613-PubMed
5.
go back to reference Pepe M: Evaluating technologies for classification and prediction in medicine. Statistics in medicine. 2005, 24: 3687-3696. 10.1002/sim.2431.CrossRefPubMed Pepe M: Evaluating technologies for classification and prediction in medicine. Statistics in medicine. 2005, 24: 3687-3696. 10.1002/sim.2431.CrossRefPubMed
6.
go back to reference Pepe M, Longton G: Standardizing diagnostic markers to evaluate and compare their performance. Epidemiology. 2005, 16 (5): 598-10.1097/01.ede.0000173041.03470.8b.CrossRefPubMed Pepe M, Longton G: Standardizing diagnostic markers to evaluate and compare their performance. Epidemiology. 2005, 16 (5): 598-10.1097/01.ede.0000173041.03470.8b.CrossRefPubMed
7.
go back to reference Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, d'Assignies M, Bergh J, Lidereau R, Ellis P, Harris A, Klijn J, Foekens J, Cardoso F, Piccart M, Buyse M, Sotiriou C, on behalf of the TRANSBIG Consortium: Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clinical Cancer Research. 2007, 13 (11): 3207-10.1158/1078-0432.CCR-06-2765.CrossRefPubMed Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, d'Assignies M, Bergh J, Lidereau R, Ellis P, Harris A, Klijn J, Foekens J, Cardoso F, Piccart M, Buyse M, Sotiriou C, on behalf of the TRANSBIG Consortium: Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clinical Cancer Research. 2007, 13 (11): 3207-10.1158/1078-0432.CCR-06-2765.CrossRefPubMed
8.
go back to reference Edgar R, Domrachev M, Lash A: Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic acids research. 2002, 30: 207-10.1093/nar/30.1.207.CrossRefPubMedPubMedCentral Edgar R, Domrachev M, Lash A: Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic acids research. 2002, 30: 207-10.1093/nar/30.1.207.CrossRefPubMedPubMedCentral
9.
go back to reference Miller L, Smeds J, George J, Vega V, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu E, Bergh J: An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proceedings of the National Academy of Sciences. 2005, 102 (38): 13550-13555. 10.1073/pnas.0506230102.CrossRef Miller L, Smeds J, George J, Vega V, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu E, Bergh J: An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proceedings of the National Academy of Sciences. 2005, 102 (38): 13550-13555. 10.1073/pnas.0506230102.CrossRef
10.
go back to reference Pawitan Y, Bjöhle J, Amler L, Borg A, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, Liu S, Miller L, Nordgren H, Ploner A, Sandelin K, Shaw P, Smeds J, Skoog L, Wédren S, Bergh J: Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Research. 2005, 7 (6): R953-10.1186/bcr1325.CrossRefPubMedPubMedCentral Pawitan Y, Bjöhle J, Amler L, Borg A, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, Liu S, Miller L, Nordgren H, Ploner A, Sandelin K, Shaw P, Smeds J, Skoog L, Wédren S, Bergh J: Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Research. 2005, 7 (6): R953-10.1186/bcr1325.CrossRefPubMedPubMedCentral
11.
go back to reference van de Vijver M, He Y, van't Veer L, Dai H, Hart A, Voskuil D, Schreiber G, Peterse J, Roberts C, Marton M, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers E, Friend S, Bernards R: A gene-expression signature as a predictor of survival in breast cancer. New England Journal of Medicine. 2002, 347 (25): 1999-2009. 10.1056/NEJMoa021967.CrossRefPubMed van de Vijver M, He Y, van't Veer L, Dai H, Hart A, Voskuil D, Schreiber G, Peterse J, Roberts C, Marton M, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers E, Friend S, Bernards R: A gene-expression signature as a predictor of survival in breast cancer. New England Journal of Medicine. 2002, 347 (25): 1999-2009. 10.1056/NEJMoa021967.CrossRefPubMed
12.
go back to reference Bild A, Yao G, Chang J, Wang Q, Potti A, Chasse D, Joshi M, Harpole D, Lancaster J, Berchuck A, Olson J, Marks J, Dressman H, West M, Nevins J: Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2005, 439 (7074): 353-357. 10.1038/nature04296.CrossRefPubMed Bild A, Yao G, Chang J, Wang Q, Potti A, Chasse D, Joshi M, Harpole D, Lancaster J, Berchuck A, Olson J, Marks J, Dressman H, West M, Nevins J: Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2005, 439 (7074): 353-357. 10.1038/nature04296.CrossRefPubMed
13.
go back to reference Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JYH, Zhang J: Bioconductor: Open software development for computational biology and bioinformatics. Genome Biology. 2004, 5: R80-10.1186/gb-2004-5-10-r80.CrossRefPubMedPubMedCentral Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JYH, Zhang J: Bioconductor: Open software development for computational biology and bioinformatics. Genome Biology. 2004, 5: R80-10.1186/gb-2004-5-10-r80.CrossRefPubMedPubMedCentral
14.
go back to reference Irizarry RA, Gautier L, Bolstad BM, with contributions from Magnus Astrand CM, Cope LM, Gentleman R, Gentry J, Halling C, Huber W, MacDonald J, Rubinstein BIP, Workman C, Zhang J: affy: Methods for Affymetrix Oligonucleotide Arrays. 2006, [R package version 1.12.2] Irizarry RA, Gautier L, Bolstad BM, with contributions from Magnus Astrand CM, Cope LM, Gentleman R, Gentry J, Halling C, Huber W, MacDonald J, Rubinstein BIP, Workman C, Zhang J: affy: Methods for Affymetrix Oligonucleotide Arrays. 2006, [R package version 1.12.2]
15.
go back to reference R Development Core Team: R: A Language and Environment for Statistical Computing. 2008, R Foundation for Statistical Computing, Vienna, Austria, [ISBN 3-900051-07-0], [http://www.R-project.org] R Development Core Team: R: A Language and Environment for Statistical Computing. 2008, R Foundation for Statistical Computing, Vienna, Austria, [ISBN 3-900051-07-0], [http://​www.​R-project.​org]
16.
go back to reference Chang H, Nuyten D, Sneddon J, Hastie T, Tibshirani R, Sorlie T, Dai H, He Y, van't Veer L, Bartelink H, van de Rijn M, Brown P, van de Vijver M: Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proceedings of the National Academy of Sciences. 2005, 102 (10): 3738-3743. 10.1073/pnas.0409462102.CrossRef Chang H, Nuyten D, Sneddon J, Hastie T, Tibshirani R, Sorlie T, Dai H, He Y, van't Veer L, Bartelink H, van de Rijn M, Brown P, van de Vijver M: Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proceedings of the National Academy of Sciences. 2005, 102 (10): 3738-3743. 10.1073/pnas.0409462102.CrossRef
17.
go back to reference Gentleman RC: annotate: Annotation for microarrays. [R package version 1.12.1] Gentleman RC: annotate: Annotation for microarrays. [R package version 1.12.1]
18.
go back to reference Cox D, Oakes D: Analysis of survival data. 1984, Chapman & Hall/CRC Cox D, Oakes D: Analysis of survival data. 1984, Chapman & Hall/CRC
19.
go back to reference Burnham K, Anderson D: Multimodel inference: understanding AIC and BIC in model selection. Sociological Methods & Research. 2004, 33 (2): 261-CrossRef Burnham K, Anderson D: Multimodel inference: understanding AIC and BIC in model selection. Sociological Methods & Research. 2004, 33 (2): 261-CrossRef
20.
go back to reference Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological). 1995, 289-300. Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological). 1995, 289-300.
22.
go back to reference Mishra G, Suresh M, Kumaran K, Kannabiran N, Suresh S, Bala P, Shivakumar K, Anuradha N, Reddy R, Raghavan T, et al: Human protein reference database-2006 update. Nucleic acids research. 2006, D411-10.1093/nar/gkj141. 34 Database Mishra G, Suresh M, Kumaran K, Kannabiran N, Suresh S, Bala P, Shivakumar K, Anuradha N, Reddy R, Raghavan T, et al: Human protein reference database-2006 update. Nucleic acids research. 2006, D411-10.1093/nar/gkj141. 34 Database
23.
go back to reference Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M, Paulovich A, Pomeroy S, Golub T, Lander E, Mesirov J: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences. 2005, 102 (43): 15545-15550. 10.1073/pnas.0506580102.CrossRef Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M, Paulovich A, Pomeroy S, Golub T, Lander E, Mesirov J: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences. 2005, 102 (43): 15545-15550. 10.1073/pnas.0506580102.CrossRef
24.
go back to reference Efron B, Tibshirani R: On testing the significance of sets of genes. Annals of Applied Statistics. 2007, 1: 107-129. 10.1214/07-AOAS101.CrossRef Efron B, Tibshirani R: On testing the significance of sets of genes. Annals of Applied Statistics. 2007, 1: 107-129. 10.1214/07-AOAS101.CrossRef
25.
go back to reference Guo W, Romano J: A generalized Sidak-Holm procedure and control of generalized error rates under independence. Statistical Applications in Genetics and Molecular Biology. 2007, 6: 10.2202/1544-6115.1247. Guo W, Romano J: A generalized Sidak-Holm procedure and control of generalized error rates under independence. Statistical Applications in Genetics and Molecular Biology. 2007, 6: 10.2202/1544-6115.1247.
26.
go back to reference Ertel A, Verghese A, Byers S, Ochs M, Tozeren A: Pathway-specific differences between tumor cell lines and normal and tumor tissue cells. Mol Cancer. 2006, 5: 55-10.1186/1476-4598-5-55.CrossRefPubMedPubMedCentral Ertel A, Verghese A, Byers S, Ochs M, Tozeren A: Pathway-specific differences between tumor cell lines and normal and tumor tissue cells. Mol Cancer. 2006, 5: 55-10.1186/1476-4598-5-55.CrossRefPubMedPubMedCentral
27.
go back to reference Liu Y, Ringnér M: Revealing signaling pathway deregulation by using gene expression signatures and regulatory motif analysis. Genome Biology. 2007, 8 (5): R77-10.1186/gb-2007-8-5-r77.CrossRefPubMedPubMedCentral Liu Y, Ringnér M: Revealing signaling pathway deregulation by using gene expression signatures and regulatory motif analysis. Genome Biology. 2007, 8 (5): R77-10.1186/gb-2007-8-5-r77.CrossRefPubMedPubMedCentral
28.
go back to reference Mazan-Mamczarz K, Hagner P, Dai B, Wood W, Zhang Y, Becker K, Liu Z, Gartenhaus R: Identification of Transformation-Related Pathways in a Breast Epithelial Cell Model Using a Ribonomics Approach. Cancer research. 2008, 68 (19): 7730-10.1158/0008-5472.CAN-08-2393.CrossRefPubMedPubMedCentral Mazan-Mamczarz K, Hagner P, Dai B, Wood W, Zhang Y, Becker K, Liu Z, Gartenhaus R: Identification of Transformation-Related Pathways in a Breast Epithelial Cell Model Using a Ribonomics Approach. Cancer research. 2008, 68 (19): 7730-10.1158/0008-5472.CAN-08-2393.CrossRefPubMedPubMedCentral
29.
go back to reference Cooper R, Perry S, Breitman T: Pyrimidine metabolism in human leukocytes. I. Contribution of exogenous thymidine to DNA-thymine and its effect on thymine nucleotide synthesis in leukemic leukocytes. Cancer Res. 1966, 26 (11): 2267-2275.PubMed Cooper R, Perry S, Breitman T: Pyrimidine metabolism in human leukocytes. I. Contribution of exogenous thymidine to DNA-thymine and its effect on thymine nucleotide synthesis in leukemic leukocytes. Cancer Res. 1966, 26 (11): 2267-2275.PubMed
30.
go back to reference Al-Rawi M, Rmali K, Watkins G, Mansel R, Jiang W: Aberrant expression of interleukin-7 (IL-7) and its signalling complex in human breast cancer. European Journal of Cancer. 2004, 40 (4): 494-502. 10.1016/j.ejca.2003.10.016.CrossRefPubMed Al-Rawi M, Rmali K, Watkins G, Mansel R, Jiang W: Aberrant expression of interleukin-7 (IL-7) and its signalling complex in human breast cancer. European Journal of Cancer. 2004, 40 (4): 494-502. 10.1016/j.ejca.2003.10.016.CrossRefPubMed
31.
go back to reference Alexe G, Alexe S, Axelrod D, Bonates T, Lozina I, Reiss M, Hammer P: Breast cancer prognosis by combinatorial analysis of gene expression data. Breast Cancer Research. 2006, 8 (4): R41-10.1186/bcr1512.CrossRefPubMedPubMedCentral Alexe G, Alexe S, Axelrod D, Bonates T, Lozina I, Reiss M, Hammer P: Breast cancer prognosis by combinatorial analysis of gene expression data. Breast Cancer Research. 2006, 8 (4): R41-10.1186/bcr1512.CrossRefPubMedPubMedCentral
32.
go back to reference Alexe G, Dalgin G, Scanfeld D, Tamayo P, Mesirov J, DeLisi C, Harris L, Barnard N, Martel M, Levine A, Ganesan S, Bhanot G: High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. Cancer research. 2007, 67 (22): 10669-10.1158/0008-5472.CAN-07-0539.CrossRefPubMed Alexe G, Dalgin G, Scanfeld D, Tamayo P, Mesirov J, DeLisi C, Harris L, Barnard N, Martel M, Levine A, Ganesan S, Bhanot G: High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. Cancer research. 2007, 67 (22): 10669-10.1158/0008-5472.CAN-07-0539.CrossRefPubMed
33.
go back to reference Györffy B, Schäfer R: Meta-analysis of gene expression profiles related to relapse-free survival in 1,079 breast cancer patients. Breast cancer research and treatment. 2009, 118 (3): 433-441. 10.1007/s10549-008-0242-8.CrossRefPubMed Györffy B, Schäfer R: Meta-analysis of gene expression profiles related to relapse-free survival in 1,079 breast cancer patients. Breast cancer research and treatment. 2009, 118 (3): 433-441. 10.1007/s10549-008-0242-8.CrossRefPubMed
34.
go back to reference Van't Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M, Peterse H, Van der Kooy K, Marton M, Witteveen A, Schreiber G, Kerkhoven R, Roberts C, Linsley P, Bernards R, Friend S: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415 (6871): 530-10.1038/415530a.CrossRef Van't Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M, Peterse H, Van der Kooy K, Marton M, Witteveen A, Schreiber G, Kerkhoven R, Roberts C, Linsley P, Bernards R, Friend S: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415 (6871): 530-10.1038/415530a.CrossRef
Metadata
Title
Comparative survival analysis of breast cancer microarray studies identifies important prognostic genetic pathways
Authors
Jeffrey C Miecznikowski
Dan Wang
Song Liu
Lara Sucheston
David Gold
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-573

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