Abstract
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. 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. 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%). The present study identified dysregulated genes that could classify breast cancer and may represent novel therapeutic targets for molecular subsets of cancers.
Highlights
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
As a quality assessment measure, we examined if the CGH arrays correctly identified the known HER-2 amplification region in patients who were HER-2 – amplified by routine FISH analysis
In 8 of these 11 cases (73%), the log 2 for the probe set [A14_P114826] corresponding to the HER-2 gene www.aacrjournals.org was >1.5, which has met our criteria for amplification based on CGH result
Summary
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. Patterns of DNA copy number alterations may define distinct subsets of breast cancers and frequent alterations in particular chromosomal locations can draw attention to genes that are functionally important in carcinogenesis Identification of these genes could allow the characterization of new oncogenic pathways and lead to the discovery of new therapeutic targets. These studies suggested that estrogen receptor (ER) – negative cancers frequently harbor losses in 5q and gains in 6p compared with hormone receptor – positive cancers [2] These earlier CGH technologies do not allow for fine mapping of copy number alterations at the individual gene level due to their low resolution; BAC arrays typically scan the genome at 1 to 2 Mb intervals. Further larger studies will determine whether such classification could complement the current gene expression based molecular classification for patient stratification in clinical trials
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
