Background: Individuals with Down syndrome (DS) have a lower risk for solid tumors and angiogenesis related diseases. DSCR1 is highly upregulated in DS patients and its product, calcipressin-1, was shown to suppress angiogenesis and reduce cancer risk. High DSCR1 expression has been reported to decrease PDAC growth and metastasis in animal models. Here, we analyzed the molecular features and clinical outcomes associated with DSCR1 gene expression in PDAC. Methods: 8352 tumor samples tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) were analyzed. Top quartile transcripts per million for DSCR1 expression were considered high (Q4) while bottom quartile low (Q1). Cell infiltration in the tumor microenvironment (TME) was estimated using QuantiSEQ. Interferon-gamma (IFG) and T-cell inflamed (TIS) signatures were calculated from RNA data. Statistical significance was determined as P-value adjusted for multiple comparisons (q< .05). Real world survival was obtained from insurance claims data (N = 4223) and Kaplan-Meier estimates were calculated. Results: DSCR1 expression was higher in primary tumors than metastases (q< .05). No significant differences were observed between high vs low DSCR1 PDAC in immune-related biomarkers (TMB, dMMR/MSI-H and PD-L1 protein), gene mutations and copy number alterations except for KRAS mutations which were more frequent in DSCR1 Q4 (93 vs 86%, Q4 vs Q1, q< .0001). Gene set enrichment analysis showed that DSCR1 high tumors were enriched in alterations of several pathways including NOTCH signaling, DNA repair, IFG response, myogenesis and adipogenesis (P< .05, false discovery rate < .25). B cells, M1 and M2 macrophages, neutrophils, NK cells, and Tregs were more abundant in the TME of tumors with high DSCR1 while dendritic cells, CD4+ T cells and monocytes were lower (q < .05). DSCR1 Q4 was associated with higher TIS score (50% inflamed vs 3.6%, q < .05) and positively associated with immune-related gene expression including CTLA4, IDO1, CD80, PD-L1, LAG3, CD86, TIM3, IFG, PD-1, and PD-L2 (fold change: 2-4, q< .0001). Overall, DSCR1 expression above median was associated with longer median OS (17 vs 11 months, HR 0.89 [0.83-0.95], P< .0001). When stratified by quartiles, DSCR1 Q4 was associated with longer time on treatment [ToT] with gemcitabine/nab-paclitaxel (HR 0.75 [0.63-0.89], P = .001), and marginal benefit on ToT (HR 0.81 [0.65-1.0]) but longer survival in FOLFIRINOX treated patients (HR 0.73 [0.58-0.92], P = .008). Conclusions: This is the first and most extensive profiling study to investigate DSCR1 expression in PDAC. Our data show a strong association between tumor DSCR1 gene expression, several pathway alterations, immune-related gene expression, TME cell infiltration and patient survival. These findings suggest DSCR1 as a candidate prognostic biomarker and as a potential treatment target in PDAC.