Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array.
OBJECTIVE
We used high-resolution oligonucleotide comparative genomic hybridization (CGH) arrays and matching gene expression array data to identify dysregulated genes and to classify breast cancers according to gene copy number anomalies.


METHODS
DNA was extracted from 106 pretreatment fine needle aspirations of stage II-III breast cancers that received preoperative chemotherapy. CGH was done using Agilent Human 4 x 44K arrays. Gene expression data generated with Affymetrix U133A gene chips was also available on 103 patients. All P values were adjusted for multiple comparisons.


RESULTS
The average number of copy number abnormalities in individual tumors was 76 (range 1-318). Eleven and 37 distinct minimal common regions were gained or lost in >20% of samples, respectively. Several potential therapeutic targets were identified, including FGFR1 that showed high-level amplification in 10% of cases. Close correlation between DNA copy number and mRNA expression levels was detected. Nonnegative matrix factorization (NMF) clustering of DNA copy number aberrations revealed three distinct molecular classes in this data set. NMF class I was characterized by a high rate of triple-negative cancers (64%) and gains of 6p21. VEGFA, E2F3, and NOTCH4 were also gained in 29% to 34% of triple-negative tumors. A gain of ERBB2 gene was observed in 52% of NMF class II and class III was characterized by a high rate of estrogen receptor-positive tumors (73%) and a low rate of pathologic complete response to preoperative chemotherapy (3%).


CONCLUSIONS
The present study identified dysregulated genes that could classify breast cancer and may represent novel therapeutic targets for molecular subsets of cancers.
Andre
Fabrice
F
Translational Research Unit, UPRES03535, Paris Sud University, Orsay, France. fandre@igr.fr
Job
Bastien
B
Dessen
Philippe
P
Tordai
Attila
A
Michiels
Stefan
S
Liedtke
Cornelia
C
Richon
Catherine
C
Yan
Kai
K
Wang
Bailang
B
Vassal
Gilles
G
Delaloge
Suzette
S
Hortobagyi
Gabriel N
GN
Symmans
W Fraser
WF
Lazar
Vladimir
V
Pusztai
Lajos
L
D044963:Biopsy, Fine-Needle; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D009841:Oligonucleotides / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
D009841:Oligonucleotides; D018719:Erb-b2 Receptor Tyrosine Kinases