Genomic architecture of IRF4 rearrangements in childhood and adult large B-cell lymphomas

Abstract Large B-cell lymphoma with interferon regulatory factor 4 (IRF4) rearrangement (LBCL-IRF4) predominantly affects children and young adults (CAYA) and presents as localized disease with excellent prognosis. Although most tumors harbor IRF4 rearrangement (IRF4-R), the existence of cryptic rearrangements has been suggested. Whether LBCL with IRF4-R in adults represents the same biological entity remains unclear. To address this question, 35 CAYA diagnosed with LBCL-IRF4 and 7 adults (aged >40 years) with LBCL with IRF4-R were investigated by an integrative molecular approach. Targeted sequencing structural variant analysis confirmed IRF4-R in 84% of investigated cases. In CAYA, an enrichment (55% vs 29% in adults) of translocations involving immunoglobulin heavy chain (IGH), with a breakpoint cluster 3′ to IRF4 (EXOC2) was observed, including a cryptic insertion of IGHM-IGHJ5 into the IRF4 locus. Novel translocations, IRF4::MIR142 in 2 CAYA (7%) and IRF4::BATF in 1 adult, were discovered. Whole-exome sequencing analysis identified unreported mutations in LBCL-IRF4 as YY1 and ZC3H12A (11% each). The high incidence of mutations affecting the B-cell receptor/NF-κB pathways in LBCL-IRF4 was confirmed in cases with diffuse component only. None of the CAYA tumors were classified by the LymphGen tool. Adult LBCL with IRF4-R showed higher levels of genetic complexity and a distinct mutational profile with mutations on KMT2D and DTX1 (43% each), and MYD88-L265P (29%), and were predicted as EZB or MCD (29% each). These differential genetic features were in line with different clinical presentations (extranodal involvement and advanced stage). In conclusion, IRF4-R architecture and mutational profile differ according to age, supporting that not all cases should be classified as LBCL-IRF4.