Molecular profiling and prognosis of spindle cell/sclerosing rhabdomyosarcoma: A report from the Chinese PPOG trial.

Abstract

11566 Background: Spindle cell/sclerosing rhabdomyosarcomas (SSRMS) is a rare variant of rhabdomyosarcoma, recognized as a distinct pathological entity in the most recent WHO classification. However, the molecular profile and clinical outcomes of patients with SSRMS remain poorly understood. The Pediatric Precision Oncology Group (PPOG) is a multicenter project aimed at characterizing tumor molecular profiles in pediatric oncology patients across China. Methods: From January 2016 to July 2024, a total of 70 patients with SSRMS were enrolled in the PPOG (NCT05076071) trial, with 57 patients meeting the criteria for clinical analysis. Targeted gene sequencing (830 DNA and 395 RNA) was conducted on tumor samples from 43 patients, while whole-transcriptome analysis was performed on tumor samples from 13 patients to assess gene expression. The Kaplan-Meier method was employed to estimate overall survival (OS) and event-free survival (EFS). Results: The median follow-up time was 48 months (range: 6.3–160.8 months). The 4-year EFS rates for patients with low risk (n = 16), intermediate risk (n = 27), and high risk (n = 14) were 92.9%, 79.3%, and 12.9%, respectively (P < 0.0001). The 4-year OS rates for these groups were 68.8%, 51.2%, and 39.7%, respectively (P = 0.2046). The 4-year EFS rates for patients aged < 10 years (n = 33) and ≥ 10 years (n = 24) were 66.7% and 31.7%, respectively (P = 0.017). The 4-year OS rates for these groups were 71.4% and 63.8%, respectively (P = 0.192). The most commonly recurrently altered genes were MYOD1 (48.8%), PIK3CA (25.6%), CDKN2A (23.3%), CDKN2B (16.3%), and IGF1R (9.3%) mutations. All 21 cases with MYOD1 mutations showed a p.L122R (c. T365G) mutation, consistent with previous reports. Gene interaction analysis shows that MYOD1 mutation frequently occur alongside CDKN2B mutation. Compared to the MYOD1 wild-type group, the MYOD1 mutant group has a significantly higher incidence of CDKN2B mutation, as well as higher rates of PIK3CA and IGF mutations, and lower rates of NOTCH1 and TP53 mutations. Eighteen fusion genes were detected in 30.2% (13/43) of SSRMS patients, with the most common being BRAF fusion (4.6%) and ROS1 fusion (4.6%). Actionable mutations were identified in 76.7% of patients, with the most frequently matched targeted therapies including PI3K inhibitors (32.3%), CDK4/6 inhibitors (21.2%), and MEK inhibitors (11.5%). Compared to the MYOD1 wild-type group, RNA differential expression analysis revealed a significant upregulation of the PI3K-AKT pathway in the MYOD1 mutant group. The infiltration levels of CD4+ T cells and macrophages in the MYOD1 mutant group were significantly higher than those in MYOD1 wild-type group. Conclusions: The MYOD1 mutant group and the MYOD1 wild-type group exhibit distinct molecular characteristics. Larger sample studies are needed to clarify the molecular features and risk stratification of SSRMS. Clinical trial information: NCT05076071 .