Abstract
This meta-analysis aims to concisely summarize the genetic landscape of splenic, nodal and extranodal marginal zone lymphomas (MZL) in the dura mater, salivary glands, thyroid, ocular adnexa, lung, stomach and skin with respect to somatic variants. A systematic PubMed search for sequencing studies of MZL was executed. All somatic mutations of the organs mentioned above were combined, uniformly annotated, and a dataset containing 25 publications comprising 6016 variants from 1663 patients was created. In splenic MZL, KLF2 (18%, 103/567) and NOTCH2 (16%, 118/725) were the most frequently mutated genes. Pulmonary and nodal MZL displayed recurrent mutations in chromatin-modifier-encoding genes, especially KMT2D (25%, 13/51, and 20%, 20/98, respectively). In contrast, ocular adnexal, gastric, and dura mater MZL had mutations in genes encoding for NF-κB pathway compounds, in particular TNFAIP3, with 39% (113/293), 15% (8/55), and 45% (5/11), respectively. Cutaneous MZL frequently had FAS mutations (63%, 24/38), while MZL of the thyroid had a higher prevalence for TET2 variants (61%, 11/18). Finally, TBL1XR1 (24%, 14/58) was the most commonly mutated gene in MZL of the salivary glands. Mutations of distinct genes show origin-preferential distribution among nodal and splenic MZL as well as extranodal MZL at/from different anatomic locations. Recognition of such mutational distribution patterns may help assigning MZL origin in difficult cases and possibly pave the way for novel more tailored treatment concepts.
Highlights
Marginal zone lymphomas (MZL) represent 7–8% [1, 2] of all lymphoid neoplasms
There is evidence that some extranodal MZL (EMZL) are associated with and dependent on chronic antigenic stimulation, either by autoantigens or by foreign pathogens, especially bacteria, that lead to accumulation of secondary mucosa-associated lymphoid tissue (MALT) in respective organs due to chronic inflammation, with this MALT serving as soil for neoplastic outgrowth [5]
Comparing mutational frequencies of EMZL occurring in different locations, several important differences could be demonstrated: Two thyroid MZL (TMZL) studies [18, 19] showed a high prevalence of TET2 mutations (61%, 11/18), which statistically significantly exceeded that in salivary gland
Summary
Marginal zone lymphomas (MZL) represent 7–8% [1, 2] of all lymphoid neoplasms. The World Health Organization (WHO) [3] subdivides MZL into three distinct entities: splenic MZL (SMZL), nodal MZL (NMZL), and extranodal MZL (EMZL) [2]. Differences of mutational frequencies between EMZL, NMZL, and SMZL entities, as well as between EMZL subentities, were compared using the two-tailed Fisher’s exact test With 13 studies, SMZL was the most comprehensively investigated entity and encompassed 58% of cases in the total cohort, whereas dural (DMZL) and cutaneous MZL (CMZL) accounted for only 3% each, and data was extracted from one publication each per these two respective sites/organs of origin
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