The Mutational Profile and Fusion Landscape of Chinese Pediatric B-Cell Lymphoblastic Lymphoma Patients
Authors: Li Yang , Jin Ling , Liu Ying , Jia Yueping , Dai Yunpeng , Yang Lihua , Liu Rong , Jiang Lian , Xu Zhongjin , Liu Ansheng , Yuan Xiaojun , Wang Jian , Zheng Qinlong , Zhang Yonghong 
Published: December 2024

#Yang li and Ling Jin contribute equally to this article.

*Corresponding to both Qinlong Zheng (zhengql@gobroadhealthcare.com) and Yonghong Zhang (zhangyongh@gobroadhealthcare.com).

Background:

B-cell lymphoblastic lymphoma (B-LBL) is a hematologic malignancy that originates from immature precursor B-cells and is less common in pediatric lymphoblastic lymphoma than T-cell lymphoblastic lymphoma. Currently, patients are stratified based on disease stage, as biological risk-factors have not yet been identified. A comprehensive understanding of B-LBL molecular status may help to improve the clinical management of these patients.

Aims:

The purpose of this study was to analyze the genetic features of Chinese pediatric B-LBL patients and to examine their associations with patient outcomes and clinical indicators.

Methods:

A total of 280 Chinese children with B-LBL treated at multiple clinical centers of the China Network for Childhood Lymphomas (CNCL) from 2017 to 2023 were included in this retrospective study. The patients were treated with a CNCL-NHL-2017-LBL treatment protocol. Targeted next-generation sequencing (t-NGS) with a panel spanning 262 lymphoma-associated genes was performed on tumor samples from 51 T-LBL patients. The associations of molecular variation with survival rates as well as with relapse and other clinical factors were analyzed.

Results:

This study enrolled a cohort of 280 pediatric patients diagnosed with B-LBL, with a median age of 5.8 years (range: 1-16 years) and a male-to-female ratio of 1.3:1. The median follow-up duration for our cohort was 43.7 months (95% CI: 38.2-49.1 months).

We analyzed the mutational landscapes, and a total of 53 driver genes with somatic mutations were identified in 51 B-LBLs. The most frequently mutated genes were NRAS (12%), followed by FLT3 (10%), IKZF1(10%), KRAS (10%), ASXL2 (8%), CREBBP (6%) and KMT2D (6%). The recurrent mutated genes in pediatric B-LBL were mainly involved in RAS signaling pathway. Survival analysis revealed that patients with KMT2D mutations had shorter OS than patients without these mutations (log-rank p=0.008).

In subsequent analysis, we collected fusion genes from 70 patients, of which the higher percentage fusion genes were TEL::AML1 (n=16, 23%), E2A::PBX1 (n=16, 23%), MLL rearranged (MLL-r, n=16, 23%), TCF3::PBX1 (n=5, 7%) and P2RY8::CRLF2 (n=5, 7%). Survival outcomes for patients with different fusion genes were analyzed, with the EFS of MLL-r positive patients being significantly worse than that of MLL-r negative patients (log-rank p&lt;0.001).

Further analysis of the distribution of gene mutations in patients with different clinical characteristics revealed that mutations in RAS pathway-related genes, including NRAS and KRAS, were detected only in patients with clinical stage IV. A high frequency of IKZF1 mutations was observed in patients with craniofacial, central nervous system (CNS), and bone marrow invasion. Additionally, the presence of P2RY8::CRLF2 in craniofacial invasion (13% vs. 3%) and E2A::PBX1 in CNS invasion (35% vs. 19%) was greater in patients with these clinical features than in those without these features. These findings suggest a correlation between genetic alterations and the severity of clinical symptoms, warranting further investigation.

Conclusion:

This study presents the first comprehensive molecular characterization of B-LBL in Chinese pediatric patients. There is a high incidence of mutations in genes involved in RAS signaling pathway in pediatric B-LBL. LYST mutations and MLL rearranged might be associated with poor outcomes in children with B-LBL.These results increase our understanding of the genetic heterogeneity of B-LBL in children and may pave the way for molecular risk adapted treatment protocols for B-LBL patients.