KRAS Mutation in Colorectal Cancer is Associated with a Stromal-Derived Gene Signature

Background: KRAS mutation in colorectal cancer (CRC) is characterized by an altered transcriptional profile when compared to wild-type (WT) KRAS tumors. The list of differentially expressed genes between KRAS mutant and WT CRC tumors is associated with a stromal fibroblast activation (SFA) signature. Here we confirm the variation of the SFA signature with KRAS mutation and infer its origin in the stromal component of the tumor using experimental models and in clinical samples.

Methods: The SFA signature was assessed in an inducible-KRAS murine CRC model using RNA-sequencing, and in a CRC cell line with and without a transduced KRAS mutant vector by microarray analysis. Moreover, RNA-sequencing of CRC patient-derived xenografts (PDXs) was used to determine whether the SFA signature was being expressed in the tumor epithelium or the surrounding stroma. Finally, we validated the expression of POSTN (SFA--gene) in large cohort of CRC cancer patients.

Results: The SFA signature was identified in the inducible-KRAS mouse model, matching human cohort observations of decreased SFA gene expression in KRAS mutant CRC. On the other hand, KRAS transduction did not recapitulate the SFA signature in a CRC cell line. RNA-seq reads for SFA signature genes in CRC PDXs data suggest that the SFA transcriptional program is associated with the stroma rather than the epithelial tumor. Finally, expression of POSTN was associated with KRAS WT in CRC cancer patient. cells.

Conclusions: KRAS mutation in CRC is associated with a gene expression signature derived from the tumor stroma. These findings suggest that KRAS mutation in the epithelial tumor cells may impact the tumor microenvironment in CRC.