Background: Regulator of Chromosome Condensation 1 (RCC1) is the only identified guanine nucleotide exchange factor for the Ras-related nuclear protein Ran and it functions in nuclear transport, cell cycle and DNA damage response. Overexpressed in several cancer types, RCC1 is associated with poor outcomes. We aim to investigate the role of aberrant RCC1 co-alterations and association with immune phenotypes and cancer outcomes. Methods: DNA (592-gene or whole exome)/RNA (whole transcriptome) sequencing was performed at Caris Life Sciences (Phoenix, AZ). Samples were stratified by RCC1 expression quartile thresholds (Q1:low, Q4:high) for small cell lung (SCLC, n=876), non-small cell lung (NSCLC, n=21603), gastric (GC, n=1908), pancreatic (PC, n=5071) and colorectal (CRC, n=14892) cancers. PD-L1+ expression was tested by IHC (22c3: ³1%; SP142: ³2+, 5%). TMB-High was defined as ³ 10 mutations/MB. Overall survival (OS) was calculated using Kaplan-Meier estimate. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (*P<0.05). Results: Median RCC1 expression was highest in SCLC (14.3 transcript per million [TPM]), followed by GC (9.9), NSCLC (9.9), CRC (9.8), and PC (6.9). TMB-high rates increased progressively with RCC1 expression in NSCLC (Q1-Q4 range: 31-41%*), GC (7-22%*) and CRC (3-13%*), consistent with dMMR/MSI-high rates in GC (5-18%*) and CRC (3-13%*). Similar trends were observed for PDL1+ rates in PC (Q1-Q4 range: 13-20%*), CRC (2-5%*) and NSCLC (55-58%*). In NSCLC, TP53 (Q1-Q4 range: 57-77%*), RB1 (7-13%*), and EGFR (10-15%*) mutations were seen more with higher RCC1 expression, while STK11 (15-10%*) and KRAS (33-21%*) mutations were seen less. In PC, TP53 mutations (Q1-Q4 range: 70-85%*) and MYC amplifications (1-4%*) were seen more with RCC1 expression, whereas ATM mutations were seen less (6-3%). In CRC, TP53 (Q1-Q4 range: 70-81%*) and APC (72-81%*) mutations were seen more with RCC1 expression, while GNAS mutations were seen less (4-2%*). In both SCLC and NSCLC, high RCC1 expression was associated with increased dendritic cell (5-6%* and .8-1.3%*, respectively) and NK cell fractions (5-6%* and 2.5-3.2%*) and decreased Treg fractions (1.8-1.3%* and 3.0-2.6%*). In pMMR/MSS CRC, high RCC1 expression was associated with increased dendritic cell (.6-.9%*), NK cell (3-4%*), neutrophil (6-8%*) and CD4 T cell fractions (1.1-1.2%*) and decreased CD8 T cell (.5-.4%*) and Treg fractions (1.9-1.7%*). High RCC1 expression was associated with worse OS in NSCLC (HR 1.3*), PC (HR 1.5*) and CRC (HR 1.3*), with a similar but not significant effect in SCLC (HR 1.2) and GC (HR 1.2). Conclusions: RCC1 expression is a negative prognostic marker in NSCLC, PC, and CRC. Further studies to investigate this at the molecular level may be a potential opportunity for novel targeted drug development.