Novel prognostic implications of complement activation in the tumour microenvironment for de novo metastatic BRAF V600E mutant colorectal cancer.

ABSTRACT

BACKGROUND: Prognosis of metastatic BRAF V600E mutant colorectal cancer (CRC) is poor, and the prognostic implications of immune contextures in the tumour microenvironment (TME) for CRC remain elusive. METHODS: We collected the primary tumour specimens and clinicopathological characteristics of patients with de novo metastatic microsatellite-stable BRAF V600E mutant CRC from two medical centres. Gene expression analysis was performed using the nCounterⓇ PanCancer Immune Profiling Panel. The Cox proportional hazards regression model was used for analysing survival outcomes in association with immune gene expression and immune cells. Our complement score was defined on the basis of the average gene expression in the selected co-expression module. RESULTS: High expression of classical and regulatory complement genes was significantly associated with poor prognosis (N = 54). A high complement score (defined as a score above the median value) indicated significantly shorter survival. The overall survival (OS) impact of the high score remained significant in multivariate analyses. Additionally, our complement score was strongly correlated with C4d expression in immunohistochemical staining and tumour-associated macrophage (TAM) M2 signatures. CONCLUSIONS: Complement activation in the TME was significantly associated with poor OS and was correlated with TAM M2 in patients with de novo metastatic BRAF V600E mutant CRC.