Recurrent molecular lesions in SMZL
| Lesion | Prevalence | Genomic location, target genes, functions, and associations | References |
|---|---|---|---|
| Copy number alterations | |||
| del(7q) | 14–44% | Under-expression of 18 genes and 8 miRNAs in the 7q32.1-32.2 MDR, rare mutations in the FLNC gene. | [29, 43–47] |
| dup(3q) | 15–34% | Breakpoints typically span 3q26-q29, associated with gains in chromosome 12, common to several MZLs. | [39, 44] |
| +12 | 8–25% | +12 is associated with worse overall survival in univariate analysis, but no correlation with event-free survival. | [43] |
| +18 | 8–23% | Mutually exclusive in samples with a 3q gain. | [39] |
| del(17p) | 8–24% | TP53 gene. Faster clearance and elimination of rituximab. | [39, 42] |
| del(13p) | 5–18% | Same as MDR in CLL. del(13q) presented a slower rate of elimination of rituximab. | [48] |
| del(14q) | 3–10% | 30–40% harbour translocations involving BCL3. | [49, 50] |
| del(6q) | 8–24% | No candidate genes were found in a small series of transformed SMZL. | [51] |
| dup(8q) | 2–20% | Associated with poor clinical outcomes if inclusive of the MYC gene locus. | [52] |
| del(8p) | 4–15% | Associates with poor outcomes. Amongst MZLs, is only common in SMZLs. | [48] |
| Somatic mutations | |||
| NOTCH2 | 10–25% | Crucial for MZ B-cells differentiation, associated with 7q deletions, KLF2 somatic mutations, and IGHV1-2*04 usage, an independent risk factor for TTFT (multivariate analysis). | [29, 53–59] |
| NOTCH1 | Approximately 5% | Mutations cause NOTCH1 activation in several mature B-cell tumours. | [60–62] |
| SPEN | Approximately 5% | Negative regulator of B lymphocyte differentiation into MZ B cells. | [63] |
| TNFAIP3 | 7–15% | Mutations resulted in a loss of NF-κB cascade inhibition in other NHLs. | [64] |
| KLF2 | 12–42% | Most frequent mutation in SMZL, KLF2 knockout murine B-cells have impaired migration and MZ differentiation, through NF-κB deregulation. | [28, 29, 56, 59, 65–68] |
| CARD11 | Approximately 5% | Involved in the BCR and NF-κB signaling pathways. | [54, 69] |
| TRAF3 | Approximately 8% | TRAF3 inactivation leads to B-cell lymphomagenesis in mice, through a non-canonical NF-κB pathway. | [70] |
| TP53 | Approximately 15% | Key tumour-suppressor that promotes cell-cycle arrest and apoptosis. Often deleted. Associated with unfavourable overall survival. | [29, 52, 71] |
| MYD88 | 5–15% | A small proportion of MYD88 mutations in SMZL are L265P (6%). Role in MZ B-cell differentiation, and its absence leads to a deficiency in their availability. Promotion of B-cell proliferation and survival by activation of NF-κB. | [72–79] |
| KMT2D | 11–15% | Frequent in all lymphoid tumours, mutants have delayed GC formation. | [80, 81] |
| CREBBP | Approximately 5% | Mutations were found to be fully clonal and likely early initiating events, like that in FL. Frequent in DLBCL and FL. Regulates enhancer networks with a crucial role in GC/post-GC cell fate decisions. | [53, 82, 83] |
BCR: B-cell receptor; SMZL: splenic marginal zone lymphoma; MZLs: marginal zone lymphomas; MDR: minimally deleted region; CLL: chronic lymphocytic leukaemia; MZ: marginal zone; NF-κB: nuclear factor kappaB; GC: gastric cancer; FL: follicular lymphoma