Integration of DNA copy number alterations and prognostic gene expression signatures in breast cancer patients.
OBJECTIVE
Several prognostic gene expression profiles have been identified in breast cancer. In spite of this progress in prognostic classification, the underlying mechanisms that drive these gene expression patterns remain unknown. Specific genomic alterations, such as copy number alterations, are an important factor in tumor development and progression and are also associated with changes in gene expression.


METHODS
We carried out array comparative genomic hybridization in 68 human breast carcinomas for which gene expression and clinical data were available. We used a two-class supervised algorithm, Supervised Identification of Regions of Aberration in aCGH data sets, for the identification of regions of chromosomal alterations that are associated with specific sample labeling. Using gene expression data from the same tumors, we identified genes in the altered regions for which the expression level is significantly correlated with the copy number and validated our results in public available data sets.


RESULTS
Specific chromosomal aberrations are related to clinicopathologic characteristics and prognostic gene expression signatures. The previously identified poor prognosis, 70-gene expression signature is associated with the gain of 3q26.33-27.1, 8q22.1-24.21, and 17q24.3-25.1; the 70-gene good prognosis profile is associated with the loss at 16q12.1-13 and 16q22.1-24.1; basal-like tumors are associated with the gain of 6p12.3-23, 8q24.21-22, and 10p12.33-14 and losses at 4p15.31, 5q12.3-13.1, 5q33.1, 10q23.33, 12q13.13-3, 15q15.1, and 15q21.1; HER2+ breast show amplification at 17q11.1-12 and 17q21.31-23.2 (including HER2 gene).


CONCLUSIONS
There is a strong correlation between the different gene expression signatures and underlying genomic changes. These findings help to establish a link between genomic changes and gene expression signatures, enabling a better understanding of the tumor biology that causes poor prognosis.
Horlings
Hugo M
HM
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Lai
Carmen
C
Nuyten
Dimitry S A
DS
Halfwerk
Hans
H
Kristel
Petra
P
van Beers
Erik
E
Joosse
Simon A
SA
Klijn
Christiaan
C
Nederlof
Petra M
PM
Reinders
Marcel J T
MJ
Wessels
Lodewyk F A
LF
van de Vijver
Marc J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic / Q000502:physiology; D011379:Prognosis