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PMID: 17925008 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer.

Genome biology ·Vol. 8 ·No. 10 ·2007-00-00 ·Pages R215

Chin SF, Teschendorff AE, Marioni JC, Wang Y, Barbosa-Morais NL, Thorne NP, Costa JL, Pinder SE, van de Wiel MA, Green AR, Ellis IO, Porter PL, Tavaré S, Brenton JD, Ylstra B, Caldas C

Abstract

The characterization of copy number alteration patterns in breast cancer requires high-resolution genome-wide profiling of a large panel of tumor specimens. To date, most genome-wide array comparative genomic hybridization studies have used tumor panels of relatively large tumor size and high Nottingham Prognostic Index (NPI) that are not as representative of breast cancer demographics. We performed an oligo-array-based high-resolution analysis of copy number alterations in 171 primary breast tumors of relatively small size and low NPI, which was therefore more representative of breast cancer demographics. Hierarchical clustering over the common regions of alteration identified a novel subtype of high-grade estrogen receptor (ER)-negative breast cancer, characterized by a low genomic instability index. We were able to validate the existence of this genomic subtype in one external breast cancer cohort. Using matched array expression data we also identified the genomic regions showing the strongest coordinate expression changes ('hotspots'). We show that several of these hotspots are located in the phosphatome, kinome and chromatinome, and harbor members of the 122-breast cancer CAN-list. Furthermore, we identify frequently amplified hotspots on 8q22.3 (EDD1, WDSOF1), 8q24.11-13 (THRAP6, DCC1, SQLE, SPG8) and 11q14.1 (NDUFC2, ALG8, USP35) associated with significantly worse prognosis. Amplification of any of these regions identified 37 samples with significantly worse overall survival (hazard ratio (HR) = 2.3 (1.3-1.4) p = 0.003) and time to distant metastasis (HR = 2.6 (1.4-5.1) p = 0.004) independently of NPI. We present strong evidence for the existence of a novel subtype of high-grade ER-negative tumors that is characterized by a low genomic instability index. We also provide a genome-wide list of common copy number alteration regions in breast cancer that show strong coordinate aberrant expression, and further identify novel frequently amplified regions that correlate with poor prognosis. Many of the genes associated with these regions represent likely novel oncogenes or tumor suppressors.

MeSH Terms
Breast Neoplasms/classification,genetics Chromosomes, Human, Pair 11/genetics Chromosomes, Human, Pair 8/genetics Female Gene Dosage/genetics Gene Expression Profiling/methods Gene Expression Regulation, Neoplastic Genomic Instability Genomics/methods Humans Nucleic Acid Hybridization/methods Oncogenes/genetics Receptors, Estrogen/metabolism
Chemicals
Receptors, Estrogen
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Chin Suet F
Breast Cancer Functional Genomics, Cancer Research UK Cambridge Research Institute and Department of Oncology University of Cambridge, Li Ka-Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. sc10021@cam.ac.uk
Teschendorff Andrew E
Marioni John C
Wang Yanzhong
Barbosa-Morais Nuno L
Thorne Natalie P
Costa Jose L
Pinder Sarah E
van de Wiel Mark A
Green Andrew R
Ellis Ian O
Porter Peggy L
Tavaré Simon
Brenton James D
Ylstra Bauke
Caldas Carlos
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Article Info
Journal
Genome biology
Abbr.
Genome Biol
ISSN
1474-760X
DOI
10.1186/gb-2007-8-10-r215
Email
sc10021@cam.ac.uk
Published
2007-00-00
Pages
R215
Language
English
Region
England
NLM ID
100960660
PMCID
PMC2246289
Subset
IM
External Links
PubMed source DOI: 10.1186/gb-2007-8-10-r215 PMC Full Text View journal details
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