Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Abstract

mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles of -mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants. A cohort of 361 DLBCL cases (94 mutant and 267 wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses. Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P-mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the same mutation. We showed that associated and MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P-mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated mutations significantly improved the survival of MYD88 L265P-mutant ABC DLBCL in our cohort. This study highlights the relative heterogeneity of -mutant DLBCL, adding to the field's knowledge of the theranostic importance of mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. .

A recurrent clonally distinct Burkitt lymphoma case highlights genetic key events contributing to oncogenesis

“…Somatic variant calling was performed by VarScan, using germline DNA as a reference. Variant annotation was performed by GenerateReports software, as previously described . To confirm some genetic variants, BL1 and BL2 tumor DNA was also analyzed using our in‐house dedicated lymphopanel, as previously reported …”

Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

“…Given the critical role of BCR/PI3K signaling in the pathogenesis of germinal center-derived lymphomas 8 such as Burkitt lymphoma (BL) and diffuse large B-cell lymphomas (DLBCL), 9,10 the occurrence of FOXO1 mutations in these malignancies is of great interest. FOXO1 mutations have been identified in up to 11% of adult DLBCL, [11][12][13][14][15][16][17][18] and FOXO1 has been identified as a driver gene in DLBCL cell lines. 15 DLBCL with mutations of the M1 residue, resulting in loss of the AKT recognition motif, or within this motif itself, have aberrant nuclear localization of FOXO1 and are associated with a poorer prognosis.…”

Authors’ Reply

“…On behalf of the Lymphoma Study Association group, we previously reported the genetic context of 94 MYD88mutated DLBCL patients. 1 This study further highlighted the strong association of the L265P variant with the activated B-cell like (ABC) signature, compared with the non-L265P mutations that distribute between the different DLBCL subtypes. We also observed frequent additional genetic abnormalities involving the NF-kB/Bruton tyrosine kinase pathway in these cases, including CARD11, TNFAIP3, or CD79B alterations, indicating that this mutation needs to be interpreted in a global genetic background.…”