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Page 92 Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04

noteworthy is the scarcity of the IGHV1-02 gene in other mature B-cell tumours, even tumours of the
[20]
spleen, such as SDRPL , suggesting that a distinctive selection process may predominate in SMZL
pathogenesis.

The majority (90%) of IGHV1-02 patients are IGHV1-02*04 [20-22] with extended restriction to the level of
polymorphic variation. Evidence of somatic hypermutation (SHM) is seen in the majority of IGHV1-02*04
SMZL cases (~95%) suggesting exposure to antigen is both important in progenitor tumour cell selection
but also relevant to ongoing evolution . IGHV1-02*04 cases carry extended VH CDR3 sequences, biased
[22]
[20]
IGHD and IGHJ gene usage, and distinct patterns of SHM . IGHV1-02 cases with allele *04 may have
unique immunogenetic features as the polymorphism encodes a tryptophan (W) residue rather than
arginine (R) at position 75 of VH FR3, with the latter playing a role in IG structural stability and
conformation. As will be discussed in more detail later, key somatic mutations and acquired copy number
changes define the disease but are also associated with specific immunological backgrounds. What is the
most notable is the enrichment of 7q deletions and KLF2 and NOTCH2 mutations in IGHV1-02*04
SMZL [23,24] . These analyses, with preliminary DNA methylation and transcriptomic studies [25,26] , suggest cases
with IGHV1-02*04 represent a distinct patient sub-group, which is likely to have emerged from a cell with a
distinct ancestry and/or unique immune activation process followed by transformation, ongoing antigen
[24]
exposure, with shared genomic lesions and poor survival .
The critical part that the BCR plays in SMZL is further emphasized by the presence of somatic
hypermutations, as only 12% of cases lack any evidence of SHM at the IGHV locus, and might be considered
truly unmutated [20,21] . The remaining cases exhibit evidence of SHM at the IGHV locus, with 38% and 50%
defined as borderline (97%-99.9% IGHV gene identity to germline) and significantly mutated (< 97% IGHV
gene identity to germline), respectively. The majority (71%) of IGHV1-02*04 cases harbour borderline levels
of SHM, often benign in nature that cluster in the framework region [20,22] . Whilst levels of SHM represent a
critically important prognostic and predictive biomarker in CLL [27,28] , their clinical utility in SMZL is less
established. Using SHM cut-offs established for CLL, although SHM levels are likely to be disease-specific,
showed no difference in progression-free and overall survival between mutated and unmutated IGHV
cases [29,30] . In contrast, we have shown that a physiological definition, based on the complete absence of SHM
(truly unmutated), is able to provide independent prognostic information, with truly unmutated cases
[24]
exhibiting reduced time to treatment . Taken together, these observations show that we continue to lack a
definitive understanding of the clinical utility of SHM in SMZL, likely the result of small patient cohorts,
heterogeneous treatment, and an inaccurate definition of the most biologically and clinically relevant SHM
cut-offs.

SOMATIC GENOMIC ABERRATIONS
The largest reported study of cytogenetic abnormalities in SMZL comprised 330 untreated cases of whom
143 had undergone splenectomy . 72% displayed an abnormal karyotype using conventional chromosomal
[31]
banding, with 50% exhibiting a complex karyotype (defined as three or more cytogenetic aberrations). The
majority of aberrations resulted in copy number abnormalities (CNAs) with chromosomal gains exceeding
losses. The most frequent gains were: 3/3q, trisomy 18 and trisomy 12 comprising 25%, 12% and 8% of
abnormal karyotypes, respectively. The commonest deletions involved 7q, 6q and 13q in 39%, 11.7% and 5%
of cases respectively [Table 1]. 18% of cases had concomitant deletion of 7q and gain of 3q in the same
karyotype. Interestingly, the use of FISH probes and single nucleotide polymorphism (SNP) arrays has
shown that the loci of genes recurrently mutated in SMZL, such as KLF2, BIRC3 and TRAP3 may also be the
site of small mono-allelic deletions [32,33] . In contrast, the potential functional consequences of trisomies,
whole arm gains or large deletions are much more difficult to elucidate. Generally, chromosomes that are