Abstract 1419: Metastasis and cancer stem cell markers identify two colorectal cancer subtypes with different molecular and clinical features
Authors: Burair Alsaihati, Shaying Zhao
Journal: Cancer Research (2019)

Abstract Introduction Colorectal cancer (CRC) falls among the top prevalent cancer types with lethal outcome both in the United States and worldwide. The heterogeneity of CRC highlights the importance of identifying molecular markers for meaningful classification and prognosis. The recently published Consensus Molecular Subtypes (CMS) represent a widely-used molecular subtyping of CRC. However, our analyses indicate that clear heterogeneity still exists in some CMSs. To better classify CRC, we performed the following study. Methods We collected from literature 19 gene markers classified as metastasis or cancer stem cell (CSC) markers in CRC. We then examined their expression in 622 CRC samples by The Cancer Genome Atlas (TCGA), and validated the findings using another published dataset, GSE39582, with 566 CRC samples. Results We found among the 19 gene markers examined, 9 genes cluster into two oppositely co-expressed groups (VEGFC, SMAD4, TNIK, ITGB1, CD44 and ALCAM in group 1 and VEGFB, OTUB1 and DLL4 in group 2). Principal component analysis and hierarchical sample clustering of theses 9 genes identify two subtypes among the samples of each CMS, particularly CMS2 and CMS4. We named the two subtypes S1, which corresponds to increased expression in group 1 genes, and S2, which corresponds to higher expression of group 2 genes. Analysis of cancer hallmarks indicates a strong enrichment of six pathways (androgen response, protein secretion, mitotic spindle, UV response down, PI3K and TGF-β signaling), a common and defining feature of the S1 subtype in all CMSs. Immune activation pathways and most immune cells are strongly enriched in the S1 subtype of CMS4 samples only. Conversely, S2 is the subtype that exhibits immune activation across CMS2 samples. Tumor microenvironment signatures indicate more lymph vessels and stromal invasion in S1 samples within CMS4. However, within CMS2, a higher leukocyte fraction and invasive signature feature the S2 subtype. The epithelial and proliferative signatures are associated with the S1 subtype in general, but more prominently within CMS2. Consistent with the invasive signature of S2 samples in CMS2, the analysis of TCGA clinical data indicates increased lymphatic invasion, metastasized tumors and worse overall survival for them. On the other hand, GSE39582 clinical data show that worse overall survival is associated with the S1 subtype in CMS4. Conclusion Each of CMS2 and CMS4 can be further divided into two subtypes, S1 and S2. While S2 may define more aggressive CMS2 cancers, S1 can be linked to worse prognosis in CMS4 patients. Citation Format: Burair Alsaihati, Shaying Zhao. Metastasis and cancer stem cell markers identify two colorectal cancer subtypes with different molecular and clinical features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1419.