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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 101

Figure 4. Putative SMZL disease subtypes. Collectively, data from different studies support a distinct sub-group of SMZL (Group 1)
driven by: IGHV1-02 usage, DNA hypo-methylation and over expression of genes involved in B-cell activation, NF-κB, and those encoding
for the polycomb repressor region, and recurrent genomic lesions (deletion of 7q and somatic mutations in KLF2 and NOTCH2). Sub-
groups 2-4 are less well supported due to a limited number of cases and lack of functional evidence. Further work is necessary to
delineate and characterise them fully. SMZL: Splenic marginal zone lymphoma; IGHV: immunoglobulin heavy chain variable region;
CNAs: copy number alterations; MZ: marginal zone; TLR: toll-like receptor; BCR: B-cell receptor.

cytogenetic and genomic landscape which overlaps that seen in other marginal zone and splenic lymphomas
but is distinguished by a higher incidence of 7q deletion, KLF2 and NOTCH2 mutations and a subgroup
characterised by high genome-wide promoter methylation. The latter, together with NOTCH2 mutations,
unmutated IGHV genes, TP53 abnormalities and a complex karyotype has been reported in one or more
studies to have an adverse prognostic significance [24,31,38] . The European Society for Medical Oncology has
recently published guidelines on the diagnosis, treatment and follow up of MZ lymphomas and while
acknowledging the potential utility of some of the molecular features listed above as biomarkers, none are
currently recommended for establishing the diagnosis, assessing prognosis or determining the timing or
choice of therapy.

There are a number of reasons for this apparent paradox; firstly there is a lack of routine access to many of
the potential novel biomarkers, secondly the rarity of SMZL and the paucity of clinical trial data dictate that
studies have been relatively small and retrospective and thirdly, many cohorts have included a large
percentage of non-splenectomised cases in whom establishing a definitive diagnosis may be difficult,
especially in cases presenting before the diagnostic features of HCL-v and SDRPL were well recognized.
Confining cohorts to cases who have undergone splenectomy overcomes this problem but excludes cases
with indolent disease not requiring treatment and those treated with other modalities. Nevertheless,
preliminary data from ongoing studies suggest that one or more combinations of IGHV1-2*04 usage,
deletion of 7q, NOTCH2 and KLF2 mutations and aberrant methylation will be sufficient to identify a