RIPK3 is a novel prognostic marker for lower grade glioma and further enriches IDH mutational status subgrouping

Abstract

Necroptosis is a necrotic-like cell death pathway in which Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) plays a central role and may induce inflammation and immunity. Lower RIPK3 levels have been correlated with a poor prognosis in breast and colorectal cancer patients. Instead, in gliomas, the most prevalent among central nervous system cancers, necrosis concurs with a more aggressive and lethal outcome, suggesting that, in these cases, necrotic-like pathways may be linked to worse prognoses. Lower-grade gliomas (LGG) exhibit highly diverse clinical behaviors, ranging from slow-paced growth to fast progression to glioblastoma yet patient outcomes cannot be fully predicted through the available markers. To date, IDH mutational status is the most broadly used prognostic marker, albeit several candidates have been proposed to refine LGG subgrouping. Here, we aimed to assess RIPK3 role as a prognostic marker for LGG patients, independently of or in combination with IDH. Using publicly available discovery (513 patients) and validation (134 patients) cohorts, we performed Kaplan Meier survival analysis and uni- and multivariate Cox regression models. RIPK3 is an independent prognostic marker in LGG patients, even when controlled by age and molecular or histological diagnostic criteria. Contrary to what was previously reported for other cancers, high RIPK3 expression levels correlates with an increased risk of death. Importantly, RIPK3 expression levels further split both the mutant and wild-type IDH patients into distinct risk groups. RIPK3 expression levels can be used in combination with IDH mutational status to better subgroup LGG patients regarding overall survival.