Running GSEA with oncogenic signature (C6)

[mai vũ]

Dear GSEA Team,

I have a question about oncogenic signature (C6). For example, RAF_UP.V1_DN means when RAF signaling is overexpressed in MC7 cell line, genes will be down-regulated. So if I apply gsea with MCF12A cell line,  RAF_UP.V1_DN is enriched, and my gsea graph running ES show: most genes are up-regulated (ES>0). So how should I interpret this result? (This means RAF signaling is over-activated or inhibited?)

Kind regards,

Mai Vu

[Anthony Castanza]

Hi Mai,

If you click through to the gene set page from your GSEA results there is typically some more information about the set. In particular for this set it is documented as; "Genes down-regulated in MCF-7 cells (breast cancer) positive for ESR1 MCF-7 cells (breast cancer) stably over-expressing constitutively active RAF1 gene." and "Profiling of MCF-7 cell lines stably overexpressing constitutively active Raf-1 as a model of overexpressed growth factor signaling, as well as control vector transfected cells (coMCF-7)."

So, in this model system (MCF-7 cells), these genes were found to be downregulated compared to control, when constitutively active RAF1 was over expressed. There is also the companion signature " RAF_UP.V1_UP" representing the opposite, genes unregulated in the same system.

As to what it means in your study where you find that this set of genes is positively enriched, it would imply that there is some opposing process that has occurred, the genes that would normally be repressed by constitutive RAF-1 activation are instead being overexpressed. I would also recommend looking at the UP set's enrichment as well to see if these genes are either not enriched, or downregualted.

This result would imply that the signaling activated by RAF-1 in the tumorigenic MCF-7 cell lines, is either not activated, or possibly opposed in your non-tumorogenic, MCF12A model system, but this is just a possible indication, a hypothesis, about what is occurring here, and I don't know what your precise experiment was. Either way, you would need additional experiments to validate the result.

Let me know if you have additional questions

-Anthony

Anthony S. Castanza, PhD

Curator, Molecular Signatures Database

Mesirov Lab, Department of Medicine

University of California, San Diego