LAUSR

We sought to characterize clinical outcomes for adult and pediatric patients with primary CNS tumors harboring DICER1 mutations or loss of DICER1. We conducted a retrospective cohort study of 98 patients who were treated between 1995 and 2020 for primary CNS tumors containing DICER1 mutations or loss of DICER1 on chromosome 14q, identified by targeted next generation sequencing. Kaplan–Meier plots and log rank tests were used to analyze survival. Cox proportional-hazards model was used for univariate and multivariable analyses for all-cause mortality (ACM). Within our cohort, the most common malignancies were grade 3/4 glioma (61%), grade 1/2 glioma (17%), and CNS sarcoma (6%). Sarcoma and non-glioma histologies, and tumors with biallelic DICER1 mutations or deletions were common in the pediatric population. Mutations occurred throughout DICER1, including missense mutations in the DexD/H-box helicase, DUF283, RNaseIIIa, and RNaseIIIb domains. For patients with grade 3/4 glioma, MGMT methylation (Hazard ratio [HR] 0.35, 95% Confidence Interval [CI] 0.16–0.73, p = 0.005), IDH1 R132 mutation (HR 0.11, 95% CI 0.03–0.41, p = 0.001), and missense mutation in the DexD/H-box helicase domain (HR 0.06, 95% CI 0.01–0.38, p = 0.003) were independently associated with longer time to ACM on multivariable analyses. DICER1 mutations or loss of DICER1 occur in diverse primary CNS tumors, including previously unrecognized grade 3/4 gliomas as the most common histology. While prior studies have described RNaseIIIb hotspot mutations, we document novel mutations in additional DICER1 functional domains. Within the grade 3/4 glioma cohort, missense mutation in the DexD/H-box helicase domain was associated with prolonged survival.