With the aim of understanding the genetic determinants that underlie the characteristic and at times predictive changes in gene expression that occur in tumours, the authors developed a genome-wide genetic linkage method. In a procedure that the authors call SLAMS (stepwise linkage analysis of microarray signatures), the linkage of prospective regulator genes is first mapped to large chromosomal regions. This is achieved by looking for correlation between a specific expression signature and copy-number changes within particular genomic regions. This linkage is subsequently validated and refined by determining whether increased expression of candidate genes from within these regions is correlated with the signature, as would be expected if increased copy number of a gene had a regulatory effect. To improve the robustness of their analysis, Adler and Lin et al. considered the coordinated behaviour of many genes in an expression signature.
The authors previously identified a 'wound response signature', which is a powerful predictor of metastasis and poor prognosis in many tumour types. SLAMS was used to identify genetic regulators of this signature in breast cancer tissue. Using 37 samples, they identifed a region on 8q that strongly associated with the wound signature. Further refinement indicated that within this region it is the MYC oncogene and CSN5 (a catalytic subunit of the COP9 signalosome) that cooperate to generate the expression signature. Consistent with this prediction, the region that contains CSN5 and MYC tends to be significantly amplified in tumours with the wound signature. Moreover, expressing MYC and CSN5 in non-transformed breast epithelium is sufficient to activate the wound signature. These cells become invasive but remain untransformed, indicating that wound signature and MYC and CSN5 expression are early markers of metastatic potential. The authors also showed that CSN5 controls the ubiquitylation and activity of MYC, providing a biochemical basis for their genetic interaction.
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