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Page 106 Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04

CONCLUSIONS
Over recent years, technological advances have provided exponential increases in sensitivity and specificity,
thereby transforming our understanding of many of the more prevalent mature B-cell tumours, providing
compelling evidence of their clinical utility and facilitating the development of cost effective diagnostic
procedures with high accuracy. In SMZL, the picture is less clear. Most cases of SMZL remain indolent with
protracted overall survival, but biomarkers are needed to help define the third of patients that exhibit
aggressive disease with the possibility of transformation to a more lethal lymphoma. The work outlined
herein has improved our understanding of the biological basis of SMZL, with key discoveries being: (1) a
highly restricted IGHV gene repertoire, including selective usage of the IGHV1-2*04 allele in 30% of cases;
(2) recurrent CNAs (deletion of 7q being the most frequent) and somatic mutations, the latter of which
appear to cluster within biologically relevant pathways, such as Notch, NF-κB, BCR and TLR signalling; and
(3) a epigenetically-defined disease sub-group with PRC2 activation.

These observations are translationally important with clear clinical utility and will help with the diagnosis
and risk-adapted patient stratification in the coming years if the appropriate testing procedures can be
agreed upon. This is a challenging aim, needing the most appropriate assays that identify the most clinically
informative immunogenetic and (epi)genomic information. In our lab, we employ two resequencing panels,
one for IGHV analysis and another to identify gene mutations associated with survival (KLF2, NOTCH2,
TP53, TNFAIP3) and those that might provide information on differential diagnosis [WM (MYD88), HCL (
BRAF), CLL (NOTCH1, SF3B1), NMZL (PTPRD), HCLv (MAP2K1)]. We spike our panel design with a
backbone of genome-wide probes (200 kb resolution) for CNA identification. Our view is that this approach
is a suitable balance between genome coverage and the sequencing depth to identify sub-clonal mutations,
with appropriate reagent and sequencing costs, and the time and computational resources required for
analysis. As our understanding of the genome increases, these gene panels could be expanded with further
prognostically relevant lesions, those that might be therapeutic targets, and those that might help monitor
response. Ultimately, it might be that comprehensive multi-omics analysis (including epigenetic profiling)
will most accurately identify patients for precision medicine, but it will need to be offset by financial savings
through selection of the most appropriate treatment choice. Independent of the technical approach, each
molecular marker would need to be validated across multiple discovery and validation cohorts, in
retrospective historical studies and in prospective clinical trials, resulting in a robust and reproducible
association with a disease outcome. Assays would then need to be analytically and clinically validated,
before international harmonization, regulatory approval, and ongoing assessment through accreditation.
Guidelines for interpretation and reporting would be required, and training would be needed to facilitate
appropriate clinical referral and accurate communication with patients.

DECLARATIONS
Authors’ contributions
Prepared the first draft of the manuscript: Jaramillo Oquendo C, Strefford JC
The assistance: Oscier D
Appraised the manuscript and contributed to the final draft: Jaramillo Oquendo C, Parker H, Oscier D,
Ennis S, Gibson J, Strefford JC

Availability of data and materials
Not applicable.

Financial support and sponsorship
Jaramillo Oquendo C funded by COLCIENCAS. Parker H is funded by the Kay Kendall Leukaemia Fund
(873). Strefford JC received funding from Cancer Research UK.