Molecular profiling of breast cancer: portraits but not physiognomy

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Abstract

Breast cancers differ in response to treatment and may have a divergent clinical course despite having a similar histopathological appearance. New technology using DNA microarrays provides a systematic method to identify key markers for prognosis and treatment response by profiling thousands of genes expressed in a single cancer. Microarray profiling of 38 invasive breast cancers now confirms striking molecular differences between ductal carcinoma specimens and suggests a new classification for oestrogen-receptor negative breast cancer. Future approaches will need to include methods for high-throughput clinical validation and the ability to analyze microscopic samples.

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Cluster analysis and display of genome-wide expression patterns.

P. T. Spellman, P. O. Brown, D Botstein … (1998)

A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.

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Tissue microarrays for high-throughput molecular profiling of tumor specimens.

Juha Kononen, Lukas Bubendorf, Anne Kallionimeni … (1998)

Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.

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High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.

D. Pinkel, R. Segraves, D. Sudar … (1998)

Gene dosage variations occur in many diseases. In cancer, deletions and copy number increases contribute to alterations in the expression of tumour-suppressor genes and oncogenes, respectively. Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes. Comparative genomic hybridization (CGH) was developed for genome-wide analysis of DNA sequence copy number in a single experiment. In CGH, differentially labelled total genomic DNA from a 'test' and a 'reference' cell population are cohybridized to normal metaphase chromosomes, using blocking DNA to suppress signals from repetitive sequences. The resulting ratio of the fluorescence intensities at a location on the 'cytogenetic map', provided by the chromosomes, is approximately proportional to the ratio of the copy numbers of the corresponding DNA sequences in the test and reference genomes. CGH has been broadly applied to human and mouse malignancies. The use of metaphase chromosomes, however, limits detection of events involving small regions (of less than 20 Mb) of the genome, resolution of closely spaced aberrations and linking ratio changes to genomic/genetic markers. Therefore, more laborious locus-by-locus techniques have been required for higher resolution studies. Hybridization to an array of mapped sequences instead of metaphase chromosomes could overcome the limitations of conventional CGH (ref. 6) if adequate performance could be achieved. Copy number would be related to the test/reference fluorescence ratio on the array targets, and genomic resolution could be determined by the map distance between the targets, or by the length of the cloned DNA segments. We describe here our implementation of array CGH. We demonstrate its ability to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.

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Author and article information

Journal

Journal ID (nlm-ta): Breast Cancer Res

Title: Breast Cancer Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Print): 2001

Publication date (Electronic): 18 December 2000

Volume: 3

Issue: 2

Pages: 77-80

Affiliations

[1 ]Department of Medical Oncology and Hematology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada

[2 ]Department of Oncology and Cambridge Institute for Medical Research/Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, Wellcome Trust/MRC Building, Cambridge, UK

Article

Publisher ID: bcr274

DOI: 10.1186/bcr274

PMC ID: 138674

PubMed ID: 11250749

SO-VID: 27045ef8-1039-46d8-96b5-9558690380fa

History

Date received : 27 September 2000

Date revision requested : 17 October 2000

Date revision received : 31 October 2000

Date accepted : 1 November 2000

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Molecular profiling of breast cancer: portraits but not physiognomy

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Karger: Oncology

Most cited references 13

Cluster analysis and display of genome-wide expression patterns.

Tissue microarrays for high-throughput molecular profiling of tumor specimens.

High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.

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