6q deletion in Waldenström macroglobulinaemia negatively affects time to transformation and survival

Abstract

Summary Deletion of the long arm of chromosome 6 (del6q) is the most frequent cytogenetic abnormality in Waldenström macroglobulinaemia (WM), occurring in approximately 50% of patients. Its effect on patient outcome has not been completely established. We used fluorescence in situ hybridisation to analyse the prevalence of del6q in selected CD19+ bone marrow cells of 225 patients with newly diagnosed immunoglobulin M (IgM) monoclonal gammopathies. Del6q was identified in one of 27 (4%) cases of IgM‐monoclonal gammopathy of undetermined significance, nine of 105 (9%) of asymptomatic WM (aWM), and 28/93 (30%) of symptomatic WM (sWM), and was associated with adverse prognostic features and higher International Prognostic Scoring System for WM (IPSSWM) score. Asymptomatic patients with del6q ultimately required therapy more often and had a shorter time to transformation (TT) to symptomatic disease (median TT, 30 months vs. 199 months, respectively, P < 0·001). When treatment was required, 6q‐deleted patients had shorter progression‐free survival (median 20 vs. 47 months, P < 0·001). The presence of del6q translated into shorter overall survival (OS), irrespective of the initial diagnosis, with a median OS of 90 compared with 131 months in non‐del6q patients (P = 0·01). In summary, our study shows that del6q in IgM gammopathy is associated with symptomatic disease, need for treatment and poorer clinical outcomes.

Cytogenetic and molecular abnormalities in Waldenström's macroglobulinemia patients: Correlations and prognostic impact

“…4 Frequency of del6q was slightly lower in our cohort than that historically reported in the literature (40%-50%) 35,36 but was concordant with the one (28/93 [30%]) identified in symptomatic WM of a recent Spanish study. 37 Although del6q and CXCR4 mutations have been suggested to be mutually exclusive, 38 we did not observe this exclusivity in our series. This difference could be due in part by the technics used for del6q identification (CBA and/or FISH vs. RQ-PCR).…”

Waldenström’s Macroglobulinemia: An Exploration into the Pathology and Diagnosis of a Complex B-Cell Malignancy

“…6q deletion (usually from 6q21 to 6q23), that can be seen by fluorescence in situ hybridization (FISH), is the most common cytogenetic abnormality reported in 30-60% of WM patients. [55][56][57][58] Such deletions are associated with more aggressive IgM gammopathies and a high probability of symptomatic transformation. 58 Chromosome 6q deletions involve genes that modulate Nuclear Factor-κB (NF-KB), BCL2, Bruton Tyrosine Kinase (BTK), apoptosis and differentiation, which could help to explain why this deletion is associated with poor clinical features and a higher risk of symptomatic evolution.…”

“…[55][56][57][58] Such deletions are associated with more aggressive IgM gammopathies and a high probability of symptomatic transformation. 58 Chromosome 6q deletions involve genes that modulate Nuclear Factor-κB (NF-KB), BCL2, Bruton Tyrosine Kinase (BTK), apoptosis and differentiation, which could help to explain why this deletion is associated with poor clinical features and a higher risk of symptomatic evolution. Other genes whose deletion could justify such relationship are genes with important regulatory functions, such as IBTK, HIVEP2, and FOXO3.…”

Time to Move to the Single-Cell Level: Applications of Single-Cell Multi-Omics to Hematological Malignancies and Waldenström’s Macroglobulinemia—A Particularly Heterogeneous Lymphoma

“…Loss of chromosome 6q is found in 40–50% of patients with WM [ 91 , 92 ] and appears to be exclusive to CXCR4 in treatment-naïve patients [ 93 ]. The increasing frequency of 6q deletions from IgM-MGUS through asymptomatic and symptomatic WM suggests that loss of genes within this region facilitates disease progression [ 84 , 91 , 93 , 94 ]. As for CXCR4 mutations, the transcriptomic profile, relative to that of solely MYD88- mutated individuals, shows diminished B-cell differentiation, downregulation of tumor suppressors overexpressed by MYD88 mutation, and alternative activation of the toll-like receptor 7 (TLR7) pathway [ 95 ].…”