We developed a computational method to characterize aneuploidy in tumor samples based on coordinated aberrations in expression of genes localized to each chromosomal region. We summarized the total level of chromosomal aberration in a given tumor in a univariate measure termed total functional aneuploidy. We identified a signature of chromosomal instability from specific genes whose expression was consistently correlated with total functional aneuploidy in several cancer types. Net overexpression of this signature was predictive of poor clinical outcome in 12 cancer data sets1,2,3,4,5,6,7,8,9,10,11,12 representing six cancer types. Also, the signature of chromosomal instability was higher in metastasis samples than in primary tumors and was able to stratify grade 1 and grade 2 breast tumors according to clinical outcome. These results provide a means to assess the potential role of chromosomal instability in determining malignant potential over a broad range of tumors.
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We thank A. Amon, D. Botstein, M. Meyerson and T. Ried for helpful suggestions, and Novartis for the NCI60 expression data. This work was supported in part by the US National Institutes of Health through grant 1PO1CA-092644-01 and the Department of Defense through grant W81XWH-04-1-0549. I.S.K. was supported in part by National Institutes of Health National Center for Biomedical Computing grant 5U54LM008748-02.
S.L.C., A.C.E. and Z.S. have applied for a patent on the diagnostic use of the chromosomal instability signature described in the manuscript.
Relationship between functional aneuploidy and DNA-based measures of chromosomal abberations. (PDF 218 kb)
Total functional aneuploidy (tFA) is a significant predictor of clinical outcome in the four breast, lung and brain cancer data sets of 18 data sets evaluated. (PDF 48 kb)
Correlation between gene expression profiles and tFA is conserved in diverse human cancer data sets. (PDF 192 kb)
The CIN signature does not generate significant predictions of clinical outcome for 6 of 18 data sets evaluated. (PDF 47 kb)
The prognostic ability of cell cycle–regulated genes is dependent on CIN score. (PDF 130 kb)
Multivariate analysis of the CIN25 and proliferation signatures revealed that CIN25 was generally more relevant for risk stratification of cancer cohorts. (PDF 27 kb)
Removal of proliferation-associated genes from the CIN signature does not impair its predictive ability for clinical outcome. (PDF 591 kb)
Top 70 genes with the highest levels of consistent correlation with tFA in three cancer-associated data sets. (PDF 112 kb)
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Carter, S., Eklund, A., Kohane, I. et al. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38, 1043–1048 (2006) doi:10.1038/ng1861
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