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Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04 Page 99

[89]
result in defects in acetylation-mediated ablation of BCL6 expression and activity of p53 . ARID1A
(BAF250a) is a component of SWI/SNF (SWItch/Sucrose Non-Fermentable) family of evolutionary
conserved, multi-subunit chromatin remodelling complexes, found mutated in various cancers and in
[90]
SMZL . SWI/SNF regulates DNA accessibility to other proteins involved in replication and repair,
allowing the activation or suppression of gene transcription . It will be interesting to investigate the
[83]
relationship between these mutations and any epigenetic fingerprint associated with the cell of origin in
SMZL.

TRANSCRIPTOMICS
At the transcriptional level, limited gene expression profiling of SMZL cases revealed the expected
signatures; most notably B-cell genes, such as those within the BCR (BTK, PKCA, NFATC1) and NF-κB (
CD40, REL, BIRC3, TRAF3) pathways, and genes critical to MZ development and migration (NOTCH2)
[25,91,92] . Existing data do not yield a robust gene expression signature for SMZL, but rather genes expressed
across aligned mature B-cell tumours. Navarro et al. constructed a gene expression classifier from a panel
[93]
of B-cell tumours, which was not able to identify distinct gene signatures for SMZL, LPL and SDRPL. Of
note though, a recent meta-analysis of gene expression profiles from SMZL, normal splenic material and
other B-cell tumours was able to define 135 genes that discriminate SMZL from other B-cell lymphomas .
[94]
It will be important to validate this early observation, through the inclusion of larger patient cohorts, cell
sub-population from the spleen and the inclusions of CBL-MZ patients to track progression to overt SMZL.

EPIGENETICS
Epigenetic modifications that are perturbed in cancer include dysregulation of higher order chromatin
structure, such as chemical modifications to histones (thereby effecting DNA positive charge, decreasing
histone/DNA affinity and altering accessibility of tertiary DNA structure), DNA methylation (regulation of
gene expression by the transfer of methyl groups onto the C5 position of cytosine) and changes to miRNA
expression patterns. These modifications are crucial mechanisms that control gene transcription, and
genome stability, and contribute to normal B-cell maturation. DNA methylation is the epigenetic mark
most well-studied in both normal and malignant B-cells, which have outlined clinically relevant changes
associated with the cell-of-origin and malignant progression itself [95-99] . Murine studies first demonstrated
the crucial importance of epigenetic modifiers in various aspects of B-cell differentiation [100,101] and more
recently, high-resolution genome-wide analysis of sorted B-cell subsets has mapped the DNA methylome
during critical stages of human B-cell development [97,102,103] . These studies suggest that the B-cells are the
lineage most defined by changes in DNA methylation with up to 30% of the human DNA methylome
modified during cell maturation, particularly global changes affecting heterochromatin, DNA repeats and
polycomb repressor regions, and specific alterations targeting lineage defining enhancers and promoters. A
number of mature B-cell tumours have been analysed at the DNA methylation level, exhibiting a global
reduction in methylation levels, principally the result of hypomethylation in heterochromatic sequences that
correlates with the maturation state of the putative founding normal cell type. Specific DNA
hypermethylation is observed in these tumours and is highly correlated with sequences known to display
polycomb repression in normal cells. Unlike other mature B-cell tumours, SMZL is under-studied at the
DNA methylation level, with only a single study published that employed microarray-based promoter
methylation and gene expression analysis, correlated with genomic and clinical outcome data .
[25]
The multicentre study performed by Arribas et al. profiled the methylation status of 27,000 promoter
[25]
CpGs in 134 DNA samples extracted from spleen derived SMZL tumour cells of high purity using the
Infinium HumanMethylation27 arrays. These data were integrated with gene expression, copy number,
somatic mutational and immunogenetic data. The authors identified a patient subgroup characterised by