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MYD88 mutational status improves classification and prognostication in DLBCL
no difference was found for non-relapse mortality, indicat- ing that mutated MYD88 is a lymphoma-specific poor prognostic factor. Routine diagnostic assessment of MYD88 mutations is likely to gain decisive importance for DLBCL since several approaches may therapeutically tar- get MYD88.45,46 Several studies have indicated that DLBCL with mutated MYD88 and/or CD79B are more sensitive to Bruton’s Tyrosine Kinase (BTK)-inhibitors.46-48 As such, the objective analysis of MYD88 mutations will not only improve diagnostic classification and prognostication, but might also enable patient selection for precision medicine such as treatment with BTK-inhibitors. However, the pre- dictive significance of mutated MYD88 with or without CD79B mutations needs to be validated in upcoming clin- ical trials, including precision medicine targeting the BCR and TLR cascades.
Finally, as a corollary of this study, we identified a novel good risk DLBCL group characterized by the absence of detected genetic aberrations. These DLBCL appeared to be highly sensitive to standard immune-chemotherapy as a first-line treatment. Future studies, employing a larger NGS targeted gene panel, may elucidate the genetic driv- ers in this group. We anticipate that there might be a par- allel with the study of Chapuy et al.,15 which identified a good-risk DLBCL group harbouring mainly aberrations in epigenetic pathways.
Studies by Rossi et al. and Kurtz et al.,49,50 have analysed liquid biopsies in DLBCL demonstrating that the muta- tional load in circulating-free tumor DNA obtained by NGS technologies reliably mirror the mutational profiles of DLBCL tissues, including mutated MYD88. Additionally, digital droplet PCR techniques enable the quantification of low amounts of mutated MYD88 in any
physiological fluid.51 Further investigation is needed to determine whether the analysis of mutated MYD88 in liq- uid biopsies prior to and during therapy will be signifi- cantly predictive for the treatment response and to estab- lish its specificity and sensitivity.
Conclusion
The present study demonstrates that the presence of MYD88 and CD79B mutations is almost mutually exclu- sive with EBV infection and MYC, BCL2, and BCL6 rearrangements, indicating distinctive molecular DLBCL subgroups that can be readily appreciated in clinical prac- tice. Mutant MYD88 showed its prognostic importance for inferior survival outcomes, even next to other genetic and clinical prognosticators and IPI. Additionally, patients lacking all analysed abberrancies represented a novel risk group with superior survival outcomes. Taken together and after validation in an independent cohort, these results provide a rationale for including MYD88 mutation- al analysis in the routine diagnostics of DLBCL, to improve classification and prognostication, as well as to guide future treatment strategies.
Acknowledgments
The authors would like to thank the involved research techni- cians, data managers and physicians for their contributions to this manuscript.
Funding
This study was supported in part by research funding from ‘Egbers Stichting AMC Foundation’, ‘Stichting Fonds Oncologie Holland’, and Lymph&Co (JSV, SFS, RAG, AHC, WK, MS, MJK, and STP).
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