High-resolution genomic profiling reveals association of chromosomal aberrations on 1q and 16p with histologic and genetic subgroups of invasive breast cancer.
OBJECTIVE
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.


METHODS
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.
Stange
Daniel E
DE
Division of Molecular Genetics, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Radlwimmer
Bernhard
B
Schubert
Falk
F
Traub
Frank
F
Pich
Andreas
A
Toedt
Grischa
G
Mendrzyk
Frank
F
Lehmann
Ulrich
U
Eils
Roland
R
Kreipe
Hans
H
Lichter
Peter
P
D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002869:Chromosome Aberrations; D022202:Chromosomes, Artificial, Bacterial; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D016000:Cluster Analysis; D004273:DNA, Neoplasm; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009361:Neoplasm Invasiveness / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm