FREQUENCY OF FUSION GENES AND THEIR CLINICAL IMPACTS IN CHINESE PEDIATRIC PATIENTS WITH T-CELL LYMPHOBLASTIC LYMPHOMA

Abstract

Y. Li, L. Jin, Q. Zheng, and Y. Zhang equally contributing authors.

Introduction: T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive malignancy with a high incidence among children and adolescents. Despite its prevalence, research on fusion genes in T-LBL, particularly their distribution and prognostic implications, remains limited. This study aimed to elucidate the frequency of fusion genes in Chinese pediatric T-LBL patients and explore their potential impact on prognosis, thereby providing new insights for clinical management.

Methods: We collected data from 552 pediatric T-LBL patients (aged ≤ 16 years) treated at multiple centers of the China Network of Childhood Lymphoma (CNCL), with fusion gene testing results available for 180 patients. Sequencing-based methods were used to detect fusion genes, and statistical analysis was performed to investigate their associations with patient clinical outcomes.

Results: Among the 180 patients analyzed, 105 (58.3%) were found to harbor fusion genes, with a total of 40 distinct fusion genes identified. The higher percentage of fusion genes were SIL::TAL1 (n = 40, 22.2%), MLL fusions (n = 20, 11.1%), TCR partner-related fusions (n = 11, 6.1%), ABL1 fusions (n = 9, 5%), NOTCH1 fusions (n = 7, 3.9%), and SET::CAN (n = 7, 3.9%) (Figure 1a). These findings highlight the genetic heterogeneity of T-LBL in pediatric patients.

Prognostic analysis revealed that patients with NOTCH1 fusions had significantly poorer event-free survival (EFS) and overall survival (OS) compared to those without NOTCH1 fusions (EFS, p < 0.0001; OS, p = 0.00013, Figure 1b,c). The identified NOTCH1 fusion types included IKZF2::NOTCH1 (n = 4, 57%), MIR142::NOTCH1 (n = 2, 29%) and IKZF1::NOTCH1 (n = 1, 14%), all of which are associated with poor outcomes. We further analyzed the relationship between NOTCH1 mutations and NOTCH1 fusions, and there was no obvious evidence of co-occurrence or mutual exclusivity between these genetic events. Notably, although NOTCH1 mutations are generally associated with favorable outcomes in pediatric T-LBL patients, the cooccurrence of NOTCH1 fusions appeared to diminish this benefit, showing a trend toward poorer prognosis (p = 0.056). These findings indicate that NOTCH1 fusions may serve as potential biomarkers for adverse prognosis in pediatric patients with T-LBL. Additionally, SIL::TAL1 and MLL fusions were observed but showed no prognostic significance in this cohort, warranting further study in larger cohorts.

Conclusion: Our study provides the comprehensive overview of fusion gene distribution in Chinese pediatric T-LBL patients and highlights the significant prognostic impact of NOTCH1 fusions. These findings provide a reference for personalized clinical treatment of pediatric T-LBL and emphasize the necessity of further research into the molecular mechanisms underlying these genetic alterations. (Yang Li and Ling Jin contributed equally, Qinlong Zheng and Yonghong Zhang contributed equally).

Keywords: non-Hodgkin (Pediatric, Adolescent, and Young Adult); diagnostic and prognostic biomarkers

No potential sources of conflict of interest.