Abstract 3175: Identification of a unique subpopulation of mesenchymal-like colorectal cancers associated with better survival (2016)

Abstract The epithelial-mesenchymal transition (EMT) has been well-recognized as an important mechanism promoting cancer cell invasion and “stemness”, metastasis and therapeutic resistance. Various types of cancers with high-EMT (mesenchymal-like) features have been correlated with poorer survival. For example, recently, an international consortium (Guinney et al, Nature Medicine, 2015) has coalesced six independent classification systems of colorectal cancers into four consensus molecular subtypes (CMSs), among which only CMS4 (mesenchymal, 23%) was associated with worse overall survival and worse relapse free survival. Here we report an analysis of 458 colorectal tumors that identified a subpopulation (n = 31, 6.8%) of mesenchymal-like colorectal cancers with unique molecular features. Surprisingly, these tumors were significantly associated with better survival. All samples underwent targeted exome sequencing of 1,321 cancer-related genes, global gene expression profiling and microsatellite instability (MSI) analysis, and were evaluated for the Kaplan-Meier survival and various additional correlation analyses. We explored gene expression signatures to measure EMT, RAS/MAPK, growth factor signaling, and mucinous characteristics. While we recently found that colorectal tumors with wild-type APC (n = 151, 33.0%) were associated with worse outcome, we identified a mucinous subpopulation of these tumors (n = 31, 20.7%) which were associated with better overall survival (p = 0.004). This subpopulation of wt APC tumors were mesenchymal-like, as indicated by its significantly higher mRNA expression of the mesenchymal marker VIM (p = 0.0001) along with a robustly higher EMT signature scores (p&amp;lt;0.0001). This is in contrast to another mucinous colorectal subpopulation, MSI tumors that are epithelial-like, also with a good survival. Moreover, unlike hyper-mutated MSI tumors, the subpopulation identified appears to be correlated with the least-mutated tumors that lack common drivers (e.g. TP53, KRAS and BRAF). Compared to other wt APC tumors, this subpopulation had lower mRNA expression of a number of “canonical” Wnt/beta-catenin targeted genes including MYC (p = 0.009), MET (p&amp;lt;0.0001), CDKN2A (p = 0.03), LGR5 (p = 0.0015), HNF1A (p = 0.003), and SOX9 (p = 0.01), while expression of other targeted genes TCF4 (p&amp;lt;0.0001), TNC (p = 0.04) and NOTCH2 (p = 0.0006) were upregulated. Furthermore, these tumors were also characterized by attenuated activation of RAS/MAPK and growth factor-mediated signaling. Taken together, we have identified a specific subpopulation of colorectal cancers with distinct biological and prognostic features, indicating that a “fine-tune” classification of colorectal cancers is necessary to improve resolution of appropriate therapy. Citation Format: Mingli Yang, Michael J. Schell, Michael V. Nebozhyn, Andrey Loboda, Timothy J. Yeatman. Identification of a unique subpopulation of mesenchymal-like colorectal cancers associated with better survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3175.