J. Huang1, M. Oshi1, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA
Introduction:
Colon cancer stem cells (CSC) have been shown to be involved with tumor formation, chemotherapy resistance, and the progression of metastatic disease. Putative CSCs include cell surface markers CD133, CD24, and CD44. The clinical relevance of CSCs are mostly based on institutional studies. Using a bioinformatics approach, we hypothesize that a combination of these CSC markers has prognostic value in a large cohort of patients with colorectal cancer.
Methods:
Clinicopathologic and gene set transcriptional data were collected from a cohort of 594 patients with colorectal cancer from The Cancer Genome Atlas. The expression of CD133, CD24, and CD44 was individually defined as “high” or “low” based on the median expression as demonstrated in the literature. The R software was used to perform statistical analyses and survival curves using Kaplan-Meier method with log-rank test. Gene Set Enrichment analysis (GSEA) was performed on hallmark genes pathways important in cancer development and progression.
Results:
Disease specific survival (DSS) and overall survival (OS) were not associated with tumors that are CD133-high or CD44-high alone. Patients with CD24-high tumors have significantly better DSS (p<0.001) and OS (p=0.04). CD24-high, CD44-high and CD133-high tumors were associated with significantly greater EGFR, KRAS and Ki67 expression (p<0.001). CD133-high tumors are not associated with conventional signaling pathways in preservation of stemness, such as NOTCH and Hedgehog signaling pathways. However, CD24 and CD44-high tumors are enriched for NOTCH signaling pathway (p=0.03). In the analysis of a combination of CSCs, there was no survival difference linked to patients with CD133-high/CD44-low tumors. Patients with CD44-high/CD24-low tumors have worse DSS (p=0.005) but no difference in OS compared to patients with CD44-low/CD24-high tumors. No specific gene sets associated with the hallmarks of cancer were significantly enriched in this group. Tumors that are CD133-high/CD24-low show significant negative enrichment of MYC targets (p<0.002), E2F targets (p= 0.03), and G2M checkpoint pathways (p= 0.04), suggesting lower proliferation in these tumors. Patients with CD133-high/CD24-low tumors have worse DSS (p = 0.004) and OS (p = 0.04), after a 10-year follow up, and are more likely to have early and late recurrences.
Conclusion:
This study uses bioinformatics data to suggest the clinical relevance of putative colon cancer stem cell markers, and demonstrates that CD133-high/CD24-low tumors may be prognostic.