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Page 102 Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04

subgroup of SMZL with clearly defined diagnostic and prognostic features. Whilst the role of minimal
[113]
residual disease monitoring in the management of SMZL patients remains unclear , (epi)genomic lesions
may have utility to track treatment response, perhaps in conjunction of the use of positron emission
tomography scans.

A further benefit of genomic analyses demonstrating the importance of dysregulated NF-κB signalling,
partially mediated through increased BCR signalling has been able to provide the rationale for clinical trials
of BTK and PI3K inhibitors in all 3 subtypes of MZL. Table 3 summarises response data for patients with
SMZL who were refractory to, or relapsed after, one or more prior therapies, usually including an anti-
CD20 antibody [114-118] . Overall response rates of 50%-65% are comparable to those seen in other MZL
subtypes. It is not yet reported whether primary acquired resistance to these agents is associated with
mutations downstream of the PI3K and BCR pathways but in vitro studies using MZL cell lines have
[119]
demonstrated synergy between copanlisib and the BCL2 inhibitor venetoclax , and that acquired
copanlisib resistance induced by prolonged exposure, was associated with decreased sensitivity to other
PI3K inhibitors and to ibrutinib and with upregulation of multiple signaling pathways .
[120]
FUTURE PERSPECTIVES
Our understanding of the molecular basis of many mature B-cell tumour types has deepened over recent
decades, principally through the systematic application of novel technologies with ever increasing resolution
and throughput. This information has revolutionized our understanding of the most prevalent mature B-
cell lymphomas, yielding novel biological pathways and mechanisms, the ultimate result being
improvements in patient stratification, management, and outcomes. In CLL and DLBCL, these studies have
included several thousand patients, studies with WGS/WES, complemented with expansive transcriptomic
and epigenomic datasets, and distilled with sophisticated computational approaches. Our understanding of
SMZL lags far behind and will require significant investment to realise the translational potential of a
granular understanding of the SMZL genome and its regulation. The next section will outline key areas for
future research focus (summarised in Figure 5), culminating with an overview of two ongoing projects that
hope to answer many of these questions.

Key research questions
The research community needs to continue to collaborate, creating bio-banked resources, with high-quality
fresh-frozen tumour material and matched normal cells. Currently, the literature does not include a single
patient with genome-wide somatic mutational data. Kiel et al. reported WGS without the analysis of
[54]
matched germ-line material, precluding a meaningful analysis of the presence of non-coding somatic
variation and the documentation of underlying molecular mechanisms, such as the presence of key
mutational signatures and regions of chromothripsis and kataegis. There is a critical need to analyse germ-
line material to identify SNPs associated with disease risk, and the profiling of sequential samples from
SMZL patients as their disease evolves, at pre-treatment, and with the development of refractory disease and
ultimately transformation. There might also be utility in using circulating free DNA as a non-invasive
approach in the management of patients and in the identification of mutations as has been done in other
lymphomas [121,122] .

Consequently, we should persist in our approach to extend our DNA methylation profiling of high-quality,
purified SMZL material from large clinically annotated cohorts reflecting the clinical and biological
heterogeneity of the disease, using high-resolution microarrays and reduced representation bisulfite
sequencing approaches. Parallel analysis of expansive published data sets and the detailed fluorescence-
activated cell sorting purification of additional normal B-cell populations that reflect both the maturation