Burkitt lymphoma (BL) is a malignant tumor in children. Although BL is generally curable, early relapse and refractoriness may occur. Some molecular indicators have been recently suggested for BL diagnosis, but large heterogeneity still exists. This study aimed at providing clinical molecular targets and methods that may help improve diagnosis and treatment of childhood BL. Only children patients were included in the study, and targeted gene sequencing was conducted to identify tumor specific mutations. The mRNA and protein level expression of potential target genes were measured by real-time PCR and immunohistochemistry. The relationship between BL specific gene mutation and differential expression with clinical features was analyzed. The results showed that i) detailed analysis of
c-MYC
/
BCL2
/
BCL6
gene loci alteration and gene expression would help in accurate diagnosis and treatment determination of childhood BL; ii) loss-of-function mutations in
SOCS1
or
CIITA
gene might be used as malignant markers for BL diagnosis and prognosis; iii) specific mutations of
CD79A
,
MYD88
,
KLF2
,
DNMT3A
and
NFKBIE
genes often concurrently existed in BL and showed association with benign clinical outcomes; iv) the high expression of
MYC
,
TCF3
and loss-of-function
ID3
genes in tumor may be potential therapeutic targets and could be used for treatment monitoring; and v) four
MYC
-translocation negative cases were re-defined as high-grade B-cell lymphoma-not otherwise specified (HGBL-NOS) but showed similar clinical outcomes and molecular features to other BL cases in the study, suggesting more studies needed to explore the molecular mechanisms and clinical significance of this provisional tumor entity.