Abstract

Characteristic patterns of gene expression measured by DNA microarrays have been used to classify tumors into clinically relevant subgroups. In this study, we have refined the previously defined subtypes of breast tumors that could be distinguished by their distinct patterns of gene expression. A total of 115 malignant breast tumors were analyzed by hierarchical clustering based on patterns of expression of 534 “intrinsic” genes and shown to subdivide into one basal-like, one ERBB2-overexpressing, two luminal-like, and one normal breast tissue-like subgroup. The genes used for classification were selected based on their similar expression levels between pairs of consecutive samples taken from the same tumor separated by 15 weeks of neoadjuvant treatment. Similar cluster analyses of two published, independent data sets representing different patient cohorts from different laboratories, uncovered some of the same breast cancer subtypes. In the one data set that included information on time to development of distant metastasis, subtypes were associated with significant differences in this clinical feature. By including a group of tumors from BRCA1 carriers in the analysis, we found that this genotype predisposes to the basal tumor subtype. Our results strongly support the idea that many of these breast tumor subtypes represent biologically distinct disease entities.

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Acknowledgments

We thank Mike Fero and Stanford Functional Genomics Facility for the production of microarrays, and Michael Whitfield for help with analysis of the data produced by using Affymetrix arrays. This research was supported by National Cancer Institute Grants CA77097 and CA85129 (to D.B. and P.O.B.) and CA58223-09A1 and CA097769-01 (to C.M.P.). T.S. is a postdoctoral fellow of the Norwegian Cancer Society. P.O.B. is an Associate Investigator of the Howard Hughes Medical Institute.

Supporting Information

Supporting Table 2 Legend
Supporting Table 2 Legend
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Supporting Figure 6 Legend
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Supporting Figure 8 Legend

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 100 | No. 14
July 8, 2003
PubMed: 12829800

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Submission history

Published online: June 26, 2003
Published in issue: July 8, 2003

Acknowledgments

We thank Mike Fero and Stanford Functional Genomics Facility for the production of microarrays, and Michael Whitfield for help with analysis of the data produced by using Affymetrix arrays. This research was supported by National Cancer Institute Grants CA77097 and CA85129 (to D.B. and P.O.B.) and CA58223-09A1 and CA097769-01 (to C.M.P.). T.S. is a postdoctoral fellow of the Norwegian Cancer Society. P.O.B. is an Associate Investigator of the Howard Hughes Medical Institute.

Authors

Affiliations

Therese Sørlie
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Robert Tibshirani
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Joel Parker
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Trevor Hastie
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
J. S. Marron
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Andrew Nobel
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Shibing Deng
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Hilde Johnsen
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Robert Pesich
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Stephanie Geisler
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Janos Demeter
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Charles M. Perou
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Per E. Lønning
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Patrick O. Brown
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
Anne-Lise Børresen-Dale
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway
David Botstein¶¶
Departments of Genetics, Health, Research and Policy, and Statistics, Statistics and Health, and Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Departments of Genetics and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Departments of Statistics and Biostatistics, University of North Carolina, Chapel Hill, NC 27599; Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; and Department of Genetics, Norwegian Radium Hospital, 0310 Oslo, Norway

Notes

¶¶
To whom correspondence should be addressed. E-mail: [email protected].
Contributed by David Botstein, May 5, 2003

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