Published on Sep. 6, 2018

Despite the advancement of available therapies (surgery, chemotherapy and immunotherapy, etc.), colorectal cancer (CRC) as the third most common cancer still remains the second leading cause of cancer-related death worldwide. Typically, CRC patients could be categorized into microsatellite stable (MSS, approximately80-85% in CRC) or microsatellite instability (MSI, approximately 10-15% in CRC) type. An extensive literature has shown that CRC patients with MSI status have more T cells in the primary tumor than those with MSS status. This is believed to contribute to the 78% of the MSI patients who had cancer progression-free survival after receiving immunotherapy (Pembrolizumab, an anti-PD-1 immunotherapy) treatment. This survival rate is significantly higher than the MSS status patients whose progression-free survival rate is only 11%.  In addition, more and more clinical evidence suggests that differences in anatomical locations should be considered for the treatment instead of looking the entire organ as a whole. We hypothesize that the distributions of survival associated immune functional genes in pathways would be varied by their MS status and anatomical locations.

To empirically test this hypothesis using an informatics approach, we utilized mRNA-seq data, clinical attributes (MS status, anatomical locations, survival days, vital status) from the The Cancer Genome Atlas (TCGA) data. A computational pipeline using R packages (edge R, survival, survminer, etc) and Reactome pathway browser was developed to perform RNA-seq differential expression analysis, survival and pathway analysis for each subsite of MSS and MSI patients. This pipeline streamlines the discovery process from thousands of differential expressed genes (DEGs) to only dozens immune DEGs which may directly impact on patients’ survival. Moreover, the pathway enrichment analysis is expected to identify pathways that may provide insights for the relationships with MS status and anatomical subsites.  Through this data-driven research, we found that a descending trend of DEGs and immune DEGs were observed from right colon cancer to rectal cancer; most of immune functional genes associated with survival were enriched in pathways belonged to adaptive immune systems and cytokine signaling in immune system of right-sided MSI patients.

These results provide better understanding for the mechanism of survival difference between MSS and MSI patients after immunotherapy treatment. It has important implication for the development of future precise treatments to the CRC patients. Future studies will focus on 1) Exploration of activated immune pathways through wet lab experiments; 2) Applying this methodology on large scales immunogenomic study in multitype cancers.