Table 2.

Frequency of mutated genes in BL tumors classified based on EBV presence and genome type

GeneEBV type 1 (N = 22)EBV type 2 (N = 8)EBV negative (N = 26)NameDescription
MYC54.5% (12)75.0% (6)73.1% (19)v-myc myelocytomatosis viral oncogene homologA TF that drives cell-cycle progression and transformation. Translocation key initiating step of BL. Hypermutated secondary to juxtaposition to IgH. Mutated in numerous cancers.
ID3a,b36.4% (8)25.0% (2)69.2% (18)Inhibitor of DNA binding 3A HLH protein lacking DNA-binding domain and functions as a negative regulator of TCF3. Mutations are inactivating which decrease TCF3 interaction.
DDX3X31.8% (7)62.5% (5)42.3% (11)DEAD (Asp–Glu–Ala–Asp) box polypeptide 3, X-linkedATP-dependent RNA helicase. DDX3X is mutated in T-cell ALL, CLL, and medulloblastoma. Decreased expression in viral hepatic cellular carcinoma.
CCND3a9.1% (2)25.0% (2)38.5% (10)Cyclin D3A regulator of progression through G1 phase during cell cycle. Loss of C terminal domain leads to constitutive activation.
SMARCA4a,c4.5% (1)37.5% (3)38.5% (10)BRG1, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4Chromatin remodeler required for transcriptional activation. Functions in B-cell maturation and maintenance of IgH and TCF3 open chromatin. Loss-of-function mutations. Also mutated in ovarian cancer.
TCF3a9.1% (2)12.5% (1)38.5% (10)Transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47)TF that plays a critical role in lymphocyte development. Mutations lead to gain of function.
TP5318.2% (4)12.5% (1)23.1% (6)Tumor protein p53Tumor suppressor that is key driver of apoptosis at cell-cycle checks. Mutations are loss of function. Ubiquitously mutated in numerous cancers.
GNA1318.2% (4)12.5% (1)15.4% (4)Guanine nucleotide binding protein, alpha 13Functions as modulator of various transmembrane signaling systems for cell migration/homing. Loss-of-function mutations.
GNAI29.1% (2)37.5% (3)15.4% (4)Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 2Involved in hormonal regulation of adenylate cyclase upstream of PI3K. Likely loss-of-function mutations. Not implicated in other cancers.
TFAP4b,c4.5% (1)50.0% (4)15.4% (4)Transcription factor AP-4 (activating enhancer binding protein 4)A TF that can also activate viral genes by binding to certain motifs. Loss-of-function mutations.
ARID1A18.2% (4)0.0% (0)11.5% (3)AT rich interactive domain 1ASWI/SNF complex protein member. Loss-of-function mutations. Mutated in gastric, NPC, ovarian, and endometrial cancer.
FBXO119.1% (2)25.0% (2)11.5% (3)F-box protein 11Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Major target is BCL-6. Loss-of-function mutations. Mutated in Hodgkin and DLBCL.
MSH60.0% (0)0.0% (0)19.2% (5)MutS homolog 6Functions in DNA mismatch repair system. Loss-of-mismatch recognition may lead to loss of cell-cycle checkpoint. Likely loss-of-function mutations. Germline mutations increase risk of multiple cancers.
PRRC2Cb,c4.5% (1)37.5% (3)3.8% (1)Proline-rich coiled-coil 2CLimited info about the function. Overexpressed in PBMCs.
BCL7A13.6% (3)12.5% (1)0.0% (0)B-cell CLL/lymphoma 7ASWI/SNF protein complex member. Mutational effects unclear. Mutated in other non-Hodgkin lymphomas.
FOXO19.1% (2)0.0% (0)7.7% (2)Forkhead box O1Key TF regulated by the PI3K/AKT pathway. Loss-of-function mutations may have a role in cell growth or escape from apoptosis. Mutated in DLBCL.
PLCG2c0.0% (0)25.0% (2)7.7% (2)Phospholipase C, gamma 2A crucial enzyme in BCR signaling upstream of the PI3K/AKT pathway. Mutated frequently in melanoma.
PRKDC9.1% (2)12.5% (1)3.8% (1)Protein kinase, DNA-activated, catalytic polypeptideFunctions in DSBR and V(D)J recombination and repair of double strand breaks. Mutation effects unclear. Mutated in DLBCL.
RAD504.5% (1)12.5% (1)7.7% (2)Double-strand break repair proteinA component of the MRN complex which functions in DSBR and through recombination or nonhomologous end joining. Likely loss of function. Mutations observed in breast and ovarian cancers.
RHOA13.6% (3)12.5% (1)0.0% (0)Ras homolog family member ARegulation of signal transduction between membrane receptors and focal adhesion molecules. Likely loss-of-function with potential for increased tumor metastasis.
RPRD29.1% (2)0.0% (0)7.7% (2)Regulation of nuclear pre-mRNA domain containing 2Involves in gene expression and transcriptional initiation pathways. Mutation effects unclear. Mutations not observed in other cancers.
  • Fisher exact test P < 0.05 was denoted by afor type 1 vs. EBV negative; bfor type 2 vs. EBV-negative BLs; cfor type 1 vs. type 2. Mutated BL tumor counts are in parentheses. Gene description and functions are from NCBI/GenBank database. Mutations in other cancers are from COSMIC database (

  • Abbreviations: TF, transcription factor; BCR, B-cell receptor; PBMCs, peripheral blood mononuclear cells; DSBR, double-stranded break repair; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; NPC, nasopharyngeal carcinoma.