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Page 100 Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04

high genome-wide promoter methylation (High-M), inferior survival, an elevated risk of histologic
transformation, and a raised prevalence of NOTCH2 mutations, 7q31-32 deletion and IGHV1-02 usage. In
addition to these distinct (immuno)genetic features, the High-M subgroup was defined by significant DNA
methylation and transcriptional disruption of genes involved epigenetic regulation. Most importantly, the
High-M subgroup exhibited hypomethylation and consequent elevated transcription of genes involved in B-
cell activation and NF-κB and those encoding for the polycomb repressor complex 2 (PRC2) components,
including EED, SUZ12 and EZH2. Hypomethylation of key PRC2 components was concomitant with
hypermethylation and reduced expression of PRC2 target genes and those with H3K27me3 marks,
supporting the hypothesis that the expression of key differentiation genes defines this High-M sub-
type [25,104] . Collectively, these data support a distinct sub-group of SMZL, driven by key IGHV usage, defined
by consistent epigenetic and genomic lesions, with the likely functional impact being dysregulated lineage
specification and cellular proliferation signalling [Figure 4]. The same study was performed parallel in vitro
experiments with the demethylating agent, decitabine, which partially rescued key tumour suppressor genes
and down-regulated survival and proliferation pathways, suggesting that the High-M sub-group might be
responsive to epigenetic therapies.

MiRNAs are a key group of short noncoding RNA molecules, approximately 22 nucleotides in length,
which anneal to mRNA target genes, principally through partial complementarity to the 3'-untranslated
region of target genes, where they repress protein translation or promote mRNA decay. Aberrant miRNA
expression is a hallmark of human tumours and across B-cell lymphomas, deregulated miRNAs have been
identified due to their impact on B-cell differentiation, and on established cancer pathways. A number of
candidate and genome-wide studies have been performed identifying novel miRNAs and those that are
[105]
casually implicated in other B-cell lymphomas, such as miR-155, miR-21 and miR-34a .

As briefly mentioned previously, several candidate miRNAs have been defined based on their proximity to
the minimal deletion region on 7q. Whilst based on limited cohorts and traditional molecular approaches,
miRNAs including miR-593, miR-129, miR-182, miR-96, miR-183, miR-335, miR-29a and miR-29b-1 have
been shown to be under-expressed in the presence of 7q deletions [106,107] . Under-expression of miR-29a and
miR-29b- on 7q, has putative roles in immune regulation, cell proliferation and B-cell differentiation. In
[92]
particular a key miR-29 target is the TCL1A gene, a gene that is over-expressed in SMZL , where miRNA
binding deactivates the oncogenic function of TCL1A. Several of these other 7q miRNAs may also
contribute to disease biology through the dysregulation of target gene expression and function; miR-129
and miR-335 have been shown to target BCL2, RB1 and BCL-w [108,109] . Beyond miRNAs located on 7q,
genome-wide studies have identified a spectrum of miRNAs, some of which target disease-relevant genes
and are associated with clinical outcome. Key studies have compared miRNA expression in SMZL vs. other
B-cell lymphoma sub-types, or by using normal/reactive spleen samples [110,111] . Bouteloup et al.
[111]
demonstrated that reduced miR-29a and elevated miR-21 levels correlate with disease aggressiveness.
[112]
Peveling-Oberhag et al. found miR-26b to be differentially expressed between SMZL arising in Hepatitis-
C (HCV)+ vs. HCV- patients, though it remains unknown to what extent miR-26b expression is associated
with SMZL pathophysiology or HCV infection. However, there is only limited concordance between these
studies, perhaps reflecting biological disease heterogeneity, but also predicated on experimental differences,
such as cohort size, experimental design, technology of choice and statistical analysis. Clearly, further
investigations are needed to identify and functionally validate causative miRNAs involved in SMZL
pathogenesis.

THE CLINICAL UTILITY OF MOLECULAR LESIONS IN SMZL
Previous sections of this review have highlighted in SMZL the biased use of the IGHV1-2*04 allele, a