Genomic profiling for clinical decision making in lymphoid neoplasms

Abstract

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. While the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses and epigenetic profiling will be discussed, as these will likely become important future tools for implementing precision medicine approaches in clinical decision-making for patients with lymphoid malignancies.

Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors

“…Emavusertib showed the strongest dose-dependent anti-proliferative activity in the Karpas1718 cell line bearing mutated MYD88. Albeit a fraction of MZL patients present MYD88 abnormalities [ 2 , 10 , 11 , 12 , 13 , 14 ], the prevalence of these mutations, in particular the L265P, is much higher in LPL, [ 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] and we cannot rule out the possibility that the cell line derives from a LPL rather than from MZL. Nonetheless, our results are in line with the previously reported activity of emavusertib in MYD88 L265P mutated ABC DLBCL cell lines [ 26 ], and they indicate that emavusertib as single agent could be explored in the population of patients with MYD88 mutated LPL or MZL.…”

“…Mutations of proteins within the TLR/IL-1R pathway can lead to an increased NF-κB activity and the promotion of cancer. For example, MYD88-L265P encoding mutations are known to occur in a fraction of the activated B cell (ABC) diffuse large B-cell lymphomas (DLBCL), in the vast majority of LPL, and in rare MZL, with differences based on the primary anatomical site [ 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. In ABC DLBCL, MYD88-L265P leads to oncogenic activation of NF-κB through TLR-MYD88-IRAK1/4-TRAF6, independent of B cell receptor (BCR)–BTK activity and establishes a pathway for potential ibrutinib resistance [ 10 ].…”

Successful CNS-Centric Therapeutic Management and Genomic Profiling of Primary Cranial Vault Diffuse Large B-Cell Lymphoma

“…Extensive genomic profiling of lymphomas is becoming more common; however, it is still not widely employed and the utility of genomic testing to predict response to therapy is limited. 24 With further genomic characterization of these tumors, we may be better equipped to individualize treatment to improve outcomes.…”

Plasma cell neoplasms and related entities—evolution in diagnosis and classification

“…MYD88 mutations in the TIR domain are found in > 90% of LPL predominantly L265P, although rarely non-L265P variants may be present [28,72]. Molecular studies for MYD88 L265P should be performed using a sensitive method as some sequencing methods may yield false negative results, especially in cases with low tumor volume [18]. A small percentage of LPL are MYD88 wild-type with alternative mutations downstream of MYD88 in the NFKB signaling pathway.…”