Distinct molecular profile of IRF4-rearranged large B-cell lymphoma

Abstract

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma–related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Experience with provisional WHO‐entities large B‐cell lymphoma with IRF4‐rearrangement and Burkitt‐like lymphoma with 11q aberration in paediatric patients of the NHL‐BFM group

“…One limitation of our method is that we defined IRF4 rearrangement as lymphomas that are positive for IRF4 break‐apart FISH. This strategy would miss approximately 10% of LBCL‐ IRF4 13 as they exhibit IRF4‐ IGH fusion but are negative for IRF4 break‐apart using commercially available probes. Hence the prevalence of IRF4 ‐rearrangement in paediatric FL/DLBCL may be even higher than the 21% reported here, if IRF4‐ IGH fusion analysis is incorporated.…”

B cell lymphoma with IRF4 rearrangement: A clinicopathological study of 13 cases

“…reported distinct molecular findings in large B cell lymphoma with IRF4 rearrangement cases. Specifically, they found these tumors commonly exhibited mutations in IRF4 and NF‐kB pathway genes including CARD11, CD79B and MYD88 25 . Using an NGS‐based approach to assess samples from six patients with this disease type, we found CARD11 mutation in Case 2.…”

Detection of new drivers of frequent B-cell lymphoid neoplasms using an integrated analysis of whole genomes

“…Functional evidence supports the implication of the transcription factor RFX7 [47][48][49][50][51][52][53] and the zinc finger protein ZFP36L1 [54] in oncogenesis. Several other genes are members of the family of known lymphoma drivers, such as CXCR5 [55], HIST2H3D [56], ID2 [57] and IRF1 [58]. Additionally, 180 regulatory regions were significantly enriched in mutations, with a significant contribution of aSHM target loci (67.7% of cases).…”