ATRX large deletions and truncating mutations are associated with primary induction chemotherapy resistance in...

ATRX alterations are adverse prognostic factors in high-risk neuroblastoma patients. However, the precise impact of distinct ATRX mutation subtypes-particularly multiexon deletions versus missense mutations-on response to standard-of-care multiagent induction chemotherapy remains poorly defined.

This multicenter retrospective cohort study evaluated newly diagnosed patients with high-risk neuroblastoma who underwent comprehensive molecular profiling and received platinum-containing multiagent induction chemotherapy between 2017 and 2022.center Following 1:2 subtype-based stratified random sampling, patients were categorized into the ATRX wild-type (WT), large deletion/truncating (LDT), and missense mutation subgroups. Multiple imputation by chained equations (MICE) and inverse probability of treatment weighting (IPTW) were applied to control for baseline confounders. The primary endpoint was the objective response rate (ORR), which was assessed by a blinded independent central review. Secondary endpoints included event-free survival (EFS), overall survival (OS), and cumulative incidence of progression (CIP).

The final weighted pseudocohort comprised 138 patients (WT, n = 92; LDT, n = 33; missense, n = 13). Compared with the WT group (71.0%), the LDT group exhibited a substantially lower ORR (36.0%; P < 0.001), with a primary induction-refractory rate of 64.0%. Patients with missense mutations demonstrated an intermediate ORR (60.0%, P = 0.285 vs. WT). At a median follow-up of 42.5 months, the LDT group had a lower 3-year EFS rate than the WT group (18.5% vs. 52.4%; P < 0.001) and a higher 3-year CIP (72.6% vs. 35.2%; subdistribution hazard ratio, 2.88; P < 0.001). The association between the LDT subtype and poor induction response persisted across clinical strata and was independent of 11q deletion or MYCN amplification status.

Large ATRX deletions and truncating mutations identify an ultrahigh-risk molecular subtype of neuroblastoma characterized by primary resistance to conventional induction chemotherapy and accelerated progression. Detailed ATRX structural-variant subtyping may facilitate the early identification of patients at high risk of primary induction failure and supports the prospective evaluation of alternative or molecularly targeted induction strategies.