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

被引:244
作者
Chin, Suet F. [1 ,2 ]
Teschendorff, Andrew E. [1 ,2 ,3 ]
Marioni, John C. [2 ,3 ,5 ]
Wang, Yanzhong [1 ,2 ]
Barbosa-Morais, Nuno L. [2 ,3 ]
Thorne, Natalie P. [2 ,3 ,5 ]
Costa, Jose L. [9 ]
Pinder, Sarah E.
van de Wiel, Mark A. [10 ,11 ,12 ]
Green, Andrew R. [6 ,7 ]
Ellis, Ian O. [6 ,7 ]
Porter, Peggy L. [2 ,4 ,10 ]
Tavare, Simon [2 ,3 ,5 ]
Brenton, James D.
Ylstra, Bauke [9 ]
Caldas, Carlos [1 ,2 ,8 ]
机构
[1] Univ Cambridge, Canc Res UK Cambridge Res Inst, Breast Canc Funct Genom, Cambridge CB2 0RE, England
[2] Univ Cambridge, Dept Oncol, Li Ka Shing Ctr, Cambridge CB2 0RE, England
[3] Univ Cambridge, Canc Res UK Cambridge Res Inst, Computat Biol Grp, Cambridge CB2 0RE, England
[4] Univ Cambridge, Canc Res UK Cambridge Res Inst, Funct Genom Drug Resistance, Cambridge CB2 0RE, England
[5] Univ Cambridge, Ctr Math Sci, Dept Appl Math & Theoret Phys, Computat Biol Grp, Cambridge CB3 0WA, England
[6] City Hosp NHS Trust, Nottingham NG5 1PB, England
[7] Univ Nottingham, Nottingham NG5 1PB, England
[8] Univ Cambridge, Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England
[9] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands
[10] Vrije Univ Amsterdam, Med Ctr, Dept Biostat, NL-1007 MB Amsterdam, Netherlands
[11] Vrije Univ Amsterdam, Dept Math, Amsterdam, Netherlands
[12] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Div Human Biol, Seattle, WA 98109 USA
关键词
D O I
10.1186/gb-2007-8-10-r215
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Background: 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. Results: 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 (EDD l, WDSOF l), 8q24.11-13 (THRAP6, DCCl, 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. Conclusion: 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.
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页数:17
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