High-Resolution Genomic Profiling Reveals Association of Chromosomal Aberrations on 1q and 16p with Histologic and Genetic Subgroups of Invasive Breast Cancer

Purpose: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread, and epidemiologic features. To elucidate the genetic basis of these differences, we analyzed copy num...

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Bibliographic Details
Published in:Clinical cancer research 2006-01, Vol.12 (2), p.345-352
Main Authors: STANGE, Daniel E, RADLWIMMER, Bernhard, LICHTER, Peter, SCHUBERT, Falk, TRAUB, Frank, PICH, Andreas, TOEDT, Grischa, MENDRZYK, Frank, LEHMANN, Ulrich, EILS, Roland, KREIPE, Hans
Format: Article
Language:English
Subjects:
Antineoplastic agents
array CGH
Biological and medical sciences
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Carcinoma, Ductal, Breast - genetics
Carcinoma, Ductal, Breast - metabolism
Carcinoma, Ductal, Breast - pathology
Carcinoma, Lobular - genetics
Carcinoma, Lobular - metabolism
Carcinoma, Lobular - pathology
Chromosome Aberrations
Chromosomes, Artificial, Bacterial
Chromosomes, Human, Pair 1 - genetics
Chromosomes, Human, Pair 16 - genetics
Cluster Analysis
comparative genomic hybridization
DNA, Neoplasm
Genome, Human
genotype-phenotype correlation
Gynecology. Andrology. Obstetrics
Humans
In Situ Hybridization, Fluorescence
Mammary gland diseases
matrix-CGH
Medical sciences
Neoplasm Invasiveness - pathology
Nucleic Acid Hybridization
Oligonucleotide Array Sequence Analysis
Pharmacology. Drug treatments
Tumors
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Summary:Purpose: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread, and epidemiologic features. To elucidate the genetic basis of these differences, we analyzed copy number imbalances that differentiate the histologic subtypes. Experimental Design: High-resolution genomic profiling of 40 invasive breast cancers using matrix-comparative genomic hybridization with an average resolution of 0.5 Mb was conducted on bacterial artificial chromosome microarrays. The data were subjected to classification and unsupervised hierarchical cluster analyses. Expression of candidate genes was analyzed in tumor samples. Results: The highest discriminating power was achieved when combining the aberration patterns of chromosome arms 1q and 16p, which were significantly more often gained in ILC. These regions were further narrowed down to subregions 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. Located within the candidate gains on 1q are two genes, FMO2 and PTGS2 , known to be overexpressed in ILC relative to invasive ductal carcinoma. Assessment of four candidate genes on 16p11.2 by real-time quantitative PCR revealed significant overexpression of FUS and ITGAX in ILC with 16p copy number gain. Unsupervised hierarchical cluster analysis identified three molecular subgroups that are characterized by different aberration patterns, in particular concerning gain of MYC (8q24) and the identified candidate regions on 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. These genetic subgroups differed with regard to histology, tumor grading, frequency of alterations, and estrogen receptor expression. Conclusions: Molecular profiling using bacterial artificial chromosome arrays identified DNA copy number imbalances on 1q and 16p as significant classifiers of histologic and molecular subgroups.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-05-1633