Multiomic Characterization of RCC1 and RCC2 Expression and Their Association With Molecular Alterations, Immune Phenotypes, and Cancer Outcomes.

Abstract

Purpose: Regulator of chromosome condensation 1 (RCC1) and RCC2 have been shown to play important roles in the regulation of cell cycle, DNA damage response, and nucleocytoplasmic transport.

Materials and methods: DNA (592-gene or whole exome) and 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 cancer (SCLC; n = 876), non-small cell lung cancer (NSCLC; n = 21,603), gastric cancer (GC; n = 1,908), pancreatic cancer (PC; n = 5,071), and colorectal cancer (CRC; n = 14,892). Statistical significance was determined using chi-square and Wilcoxon rank-sum tests and adjusted for multiple comparisons (*P < .05). Corresponding analyses were run for RCC2.

Results: Median RCC1 mRNA 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). Similar to RCC1, the median RCC2 expressions were highest in SCLC (36.2 TPM). Tumor mutational burden-high rates were positively associated with increasing RCC1 expression quartiles (Q1-4) in NSCLC (31%-41%), GC (7%-22%), and CRC (5%-17%) and with increasing RCC2 expression in NSCLC and CRC only. Higher expression with RCC1 and RCC2 was associated with worse overall survival in NSCLC (hazard ratio [HR] for RCC1 and RCC2 were 1.3 and 1.3, respectively), PC (HR for RCC1 and RCC2 were 1.5 and 1.12, respectively), and CRC (HR for RCC1 and RCC2 were 1.3 and 1.03, respectively).

Conclusion: RCC1 and RCC2 expression is a negative prognostic marker in NSCLC, PC, and CRC. Further studies to investigate RCC1 and RCC2 function at the molecular level may provide opportunities for novel targeted drug development.