LAUSR

528 Background: Dysregulation of DNA mismatch repair pathway can lead to microsatellite instability in many GI tumors, and microsatellite instability is an important diagnostic and prognostic marker. Microsatellite instable (MSI) tumors comprise about 15% of colorectal malignancies and can be found in other gastrointestinal (GI) tumor types. We present results of analysis of genomic and immune infiltration differences between MSI and microsatellite stable (MSS) GI tumors spanning multiple cancer types. Methods: A total of 521 GI patients with deep whole exome sequencing (WES) of tumor and blood samples, and whole transcriptomic sequencing (RNA-Seq) (∼200M reads per tumor) were available for this analysis from a commercial database. Variant calling was performed through joint probabilistic analysis of tumor and normal DNA reads, with germline status of variants being determined by heterozygous or homozygous alternate allele fraction in the germline sample. Results: Gene expression and pathway analysis found significantly higher immune signaling in MSI cohort and higher metabolic signaling in MSS cohort. We also found upregulation of structural cellular integrity pathways in MSI tumors. Per-sample deconvolution of immune infiltration using cell type gene markers shows some MSI samples with high CD8 T-cells. Co-expression analysis of checkpoint and TME genes shows higher correlation of FOXP3 and CTLA4 in the MSS cohort compared to the MSI samples, whereas correlation between FOXP3 and PDL1 is decreased. TIM3, LAG3, and OX40 are significantly more expressed in MSI samples than MSS samples. Within the subset of colorectal tumors, additional checkpoints are significantly differentially overexpressed in MSI malignancies. 50 somatic variants are significantly differential in MSI tumors. Conclusions: MSI tumors demonstrably exhibit higher immune signaling, with many immune and checkpoint markers expressed at higher levels in MSI tumors. Some cellular integrity pathways also appear to be up in MSI cohort. A number of potentially important somatic variants are associated with MSI samples.