Genetic evaluation of encorafenib-associated kinases RAF1 and MAPK8 in pancreatic cancer: Exploratory mediation by circulating immune traits.

OBJECTIVES: Pancreatic cancer (PC) is a highly lethal malignancy, and identifying actionable therapeutic targets remains crucial. RAF1 and MAPK8 are kinases linked to the in vitro pharmacological profile of encorafenib. This study investigated the associations of genetically proxied RAF1 and MAPK8 expression with PC risk and explored the potential mediating role of circulating immune traits. METHODS: We implemented a two-sample, two-step Mendelian randomization framework integrating expression quantitative trait locus data for RAF1 and MAPK8 with genome-wide association study data for PC and 731 immune cell phenotypes. Causal estimates were primarily derived using inverse-variance weighting, and mediation analysis assessed possible immune cell-dependent effects. A phenome-wide association study (PheWAS) evaluated potential genetic pleiotropy. RESULTS: Genetically proxied RAF1 expression (OR = 0.748, 95% CI: 0.633-0.882, P = 0.001) and MAPK8 expression (OR = 0.829, 95% CI: 0.740-0.929, P = 0.001) were significantly associated with a lower risk of PC. An activated and resting CD4+ regulatory T-cell-related phenotype showed a possible partial mediating effect. The estimated mediation proportions were 16.202% for MAPK8 and 10.607% for RAF1, suggesting that Treg-related immune variation may account for part of these associations. In the PheWAS analysis, no association reached the prespecified significance threshold, and no broad genetic pleiotropic signal was detected. CONCLUSIONS: This study provides genetic evidence linking RAF1 and MAPK8 to PC risk. A circulating regulatory T-cell-related phenotype showed exploratory evidence of a possible partial contribution. These findings support further functional and pharmacological investigation of RAF1- and MAPK8-related pathways in pancreatic cancer.