Page 26 - Read Online

Page 98 Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04

Table 2. Examples of key recurrently mutated genes in SMZL
Gene Frequency Target pathway/clinico-biological associations
KLF2 12%-42% MZ B-cell homing/NF-κB signaling
Associated with 7q deletions, NOTCH2 somatic mutations and IGHV1-02*02 usage
[24]
Associated with reduced TTFT in univariate analysis
NOTCH2 10%- 25% NOTCH pathway/marginal zone development
Worse OS in univariate analysis. Associated with 7q deletions, KLF2 somatic mutations and IGHV1-02*04 usage
Independent risk factor for TTFT (multivariate analysis) [24]
TP53 ~15% Cell cycle control/genome maintenance
Associated with shorter EFS in univariate analysis but is an independent risk factor for OS (multivariate analysis) [24,38]
TNFAIP3 7%-15% Canonical NF-κB signaling/MZ differentiation
Higher frequency in small number of transformed cases [24]
MYD88 5%-15% TLR and BCR signaling/MZ differentiation
Somatic mutations associated with longer OS in univariate analysis [24]
Mutually exclusive to 7q deletion, KLF2 somatic mutations and IGHV1-02*04 usage [24]
KMT2D 11%-15% Chromatin remodeling - H3K4 methylation
High prevalence in other lymphomas particularly FL and DLBCL
TRAF3 ~8% Non canonical NF-κB signaling/marginal zone B-cell development
BIRC3 5%-11% Non canonical NF-κB signaling/marginal zone B-cell development
NOTCH1 ~5% Notch pathway/marginal zone B-cell development
Recurrently mutated in CLL where truncation of the PEST domain causes constitutive Notch activation
SPEN ~5% Notch pathway/marginal zone B-cell development
CARD11 ~5% BCR and NF-κB signaling/Marginal zone B-cell development
CREBBP ~5% Chromatin remodeling - BCL6 and p53 acetylation (germinal centre development)
MZ: Marginal zone; TTFT: time to first treatment; OS: overall survival; EFS: event free survival; TLR: toll-like receptor; BCR: B-cell receptor; FL:
follicular lymphoma; DLBCL: diffuse large B-cell lymphoma; CLL: chronic lymphocytic leukemia.

Toll-like receptor (TLR) signalling plays a key role in SMZL biology, as cellular proliferation is driven by
TLR activation. MYD88, an adaptor protein essential for proper TLR signal transduction, has several
structural domains including a death domain responsible for oligomerization and interactions with IRAK1-
4, which together lead to activation of NF-κB. The toll/interleukin-1 receptor homology (TIR) domain, at
the proteins C-terminus, is responsible for the activation of downstream signalling. MYD88 mutations have
been identified in 3%-15% of SMZL and 10% of CBL-MZ as well as across a spectrum of other B-cell
[24]
tumours where they occur as early clonal events, mutually exclusive to other driver mutations and in the
presence of mutated IGHV genes, suggesting that these mutations define a group of homogeneous disease
subtypes [23,80] . MYD88 also harbours a recurrent variant (L265P) in the TIR domain, frequently seen in a
number of mature B-cell tumours . This missense mutation promotes cell survival by enhancing NF-κB
[81]
[82]
signalling . As in CLL, MYD88 mutations have also been shown to be linked to favourable clinical
outcome in SMZL using univariate approaches, though its independent prognostic relevance has yet to be
confirmed [24,80] .

Chromatin remodelling enzymes are dynamic modulators of cell identity and regulate B-cell differentiation
and proliferation through recognition of a spectrum of specific biochemical marks on histone proteins and
DNA, thereby modifying chromatin accessibility to transcription machinery proteins . Recurrent somatic
[83]
mutations in chromatin remodelling and epigenetic modifier genes (KMT2D 11%-15%, CREBBP ~5%,
ARID1A ~4%, EP300 ~2% and TBL1XR1 ~1%) are present in ~40% of SMZL cases [24,56,57,72,84] . CREBBP
mutations are often clonal mutations in SMZL . Whilst the functional consequences of these mutations
[24]
have not been functionally validated in SMZL, there is ample evidence in other B-cell lymphomas.
Mutations in KMT2D (MLL2), a histone methyltransferase that modifies lysine-4 of histone 3, contribute to
lymphomagenesis , with an established tumour suppressor role in DLBCL and FL [86-88] . In these same
[85]
tumours, mutations in CREBBP, and more rarely, EP300, two highly similar histone acetyltransferases,