Abstract
This meta-analysis aimed to assess the impact of genetic mutations, particularly in the NOTCH2 and TNFAIP3 genes, on the prognostic outcomes of Marginal Zone Lymphoma (MZL) patients. Databases, including PubMed, Embase, and Cochrane Library, were explored up to October 2023. A total of 11 studies encompassing 2,314 records were included. Outcome measures were 5-year overall survival rates (OSR), progression-free survival rates (PFSR), and tumor progression rates (TPR). NOTCH2 and TNFAIP3 mutations were prominently identified across studies. In splenic MZL (SMZL) patients with NOTCH2 mutations, there was a significant decrease in the 5-year OSR (SMD: -11.11, 95% CI: -13.39 to -8.84, P < 0.01) and PFSR (SMD: -23.49, 95% CI: -28.85 to -18.14, P < 0.01). Similarly, TNFAIP3 mutations in SMZL patients demonstrated diminished 5-year OSR (SMD: -14.78, 95% CI: -18.01 to -11.56, P < 0.01) and PFSR (SMD: -21.06, 95% CI: -27.13 to -14.98, P < 0.01). For ocular adnexal MZL (OA-MZL) patients with NOTCH2 mutations, the 5-year OSR significantly declined (SMD: -23.40, 95% CI: -28.87 to -17.93, P < 0.01). Genetic mutations, notably in NOTCH2 and TNFAIP3 genes, have discernable negative implications on the prognosis of MZL patients. Recognizing these genetic markers can guide more personalized therapeutic interventions and inform clinical prognosis.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00277-024-06175-z.
Keywords: Genetic alterations, Prognostic impact, Marginal zone lymphoma, Meta-analysis
Introduction
Marginal Zone Lymphoma (MZL) stands as a heterogeneous group of non-Hodgkin lymphomas originating from the marginal zone B-cells present within lymph nodes and other lymphatic tissues [1]. MZL is taxonomically divided into three distinct entities, namely extranodal MZL of mucosa-associated lymphoid tissue (MALT), nodal marginal zone lymphoma (NMZL), and splenic marginal zone lymphoma (SMZL). Each of these exhibits’ unique clinical presentations and genetic features [2].
With advancements in high-throughput sequencing technologies, we have delved deeper into the genetic alterations associated with MZL. These genetic changes encompass mutations, copy number variations, and epigenetic modifications, all of which play pivotal roles in the pathogenesis of MZL [3]. However, the repercussions of these genetic alterations on the prognosis of MZL remain a partially uncharted domain.
Emerging studies have started to unveil the relationships between specific genetic alterations and the prognosis of MZL. For instance, mutations in certain genes have been linked to poorer outcomes, while alterations in others portend a more favorable prognosis [4, 5]. Gene expression analysis has further demarcated different subgroups within MZL, each with divergent prognostic outcomes [4]. A study focusing on NMZL highlighted a rare case wherein a patient exhibited atypical chylous effusions, underscoring the clinical diversity within MZL and signifying the need for deeper comprehension of its association with genetic alterations [6]. Specifically, targetable mutations such as those in the NOTCH2 and TNFAIP3 genes have been identified in MZL, offering opportunities for targeted therapies [7]. Moreover, recent breakthroughs have recognized the significance of mutations in the KLF2 gene, further underscoring the genetic complexity and therapeutic potential for MZL [8].
In this meta-analysis, we aim to synthesize recent research advancements to discern the implications of genetic alterations on the prognosis of MZL. By doing so, we aspire to pave the way for more targeted and individualized therapeutic strategies for MZL patients.
Methods
Search strategy
To methodically assess genetic alterations and their prognostic ramifications in MZL, we designed an exhaustive and rigorous search strategy. With PRISMA guidelines as our beacon, prominent databases such as PubMed, Embase, the Cochrane Library, and Google Scholar underwent in-depth exploration. The keyword cluster comprised terms like ‘Marginal Zone Lymphoma’, ‘genetic alterations’, ‘prognosis’, ‘epigenetic modifications’, and ‘mutation implications’. The search was anchored to harness studies up to October 2023, with an exclusive preference for English language publications. An initial distillation was achieved by skimming through titles and abstracts, which subsequently paved the way for a deeper analysis of relevant articles’ full content.
Criteria for study inclusion and exclusion
Our focus remained steadfast on studies that illuminated the relationship between genetic alterations and prognosis within the context of Marginal Zone Lymphoma. Randomized controlled trials, especially those shedding light on distinct genetic modifications and their consequent clinical outcomes, were particularly sought after. We sidestepped studies devoid of a pronounced focus on MZL genetic alterations, as well as genres such as reviews, case observations, and commentaries. The initial evaluation was confined to abstracts and titles, but qualifying studies were subjected to a more thorough inspection. In instances of selection discordance, mutual consultations facilitated a consensus.
Data aggregation
To harness the full spectrum of relevant insights, we adopted a structured data compilation regimen. This entailed recording pivotal details like the principal investigator, study locale, publication year, and the methodological blueprint. Demographic parameters, particularly age group delineations, were meticulously logged. Furthermore, we paid close attention to the interventions explored, the outcomes presented, and the nuanced impact of specific genetic deviations on MZL prognosis.
Statistical analysis
Grounding our analytical pursuits was the Review Manager (RevMan) software, an apt choice given its precision in meta-analytical studies. For continuous data realms, interpretations were based on either the mean difference (MD) or the standardized mean difference (SMD), each accompanied by its 95% confidence intervals (CIs). Dichotomous datasets were deciphered through risk ratio (RR) or odds ratio (OR) metrics, with pertinent 95% CIs. The I² statistic, pivotal in gauging study-to-study variability, was employed, designating a P-value of less than 0.05 as the benchmark for statistical significance.
Evaluation of publication bias
To shield our findings from potential biases, we relied on the tried-and-tested Cochrane Risk of Bias tool. Each study underwent a dual-evaluation, with two independent reviewers systematically examining them across diverse domains to unearth potential biases. These were subsequently categorized for clarity. The vigil against publication bias was maintained through tools like funnel plots, sensitivity evaluations, and the employment of Egger’s regression test, ensuring that our analysis remained both rigorous and trustworthy.
Results
Study selection and characteristics
The process for literature search and study selection is illustrated in Fig. 1. An initial screen of 2,314 records identified 276 full-text articles, of which 11 [3, 9–18] were deemed suitable for meta-analysis, focusing on genetic alterations and their prognostic implications in MZL. Detailed characteristics for these studies can be found in Table 1.
Fig. 1.
Flow diagram illustrating the literature search and study selection process
Table 1.
Detailed characteristics of the selected studies
| Study | Year | Number of cases used in this study | MZL type | Most frequently mutated genes & Functional changes caused by gene mutations | Pathological examination | Prognostic outcomes |
|---|---|---|---|---|---|---|
| Parry et al., | 2015 | 175 | Splenic marginal zone lymphoma (SMZL) |
TNFAIP3 45%, Loss of function NOTCH2 36%, Gain of function TLBXR1 36%, Loss of function EP300 18%, Gain of function KLHL6 18%, Loss of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Progression-free survival rates (PFSR) |
| Piva et al., | 2015 | 96 | Splenic marginal zone lymphoma (SMZL) |
TBL1XR1 24%, Loss of function TNFAIP3 16%, Loss of function NOTCH2 11%, Gain of function SPEN 11%, Gain of function KMT2C 11%, Loss of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Tumor progression rate (TPR) |
| Clipson et al., | 2015 | 105 | Splenic marginal zone lymphoma (SMZL) |
TNFAIP3 39%, Loss of function KMT2D 15%, Loss of function CREBBP 10%, Loss of function NOTCH2 10%, Gain of function MYD88 10%, Gain of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Tumor progression rate (TPR) |
| Campos-Martin et al., | 2017 | 84 | Splenic marginal zone lymphoma (SMZL) |
KMT2D 25%, Loss of function TNFAIP3 18%, Loss of function PRDM1 12%, Loss of function NOTCH2 12%, Gain of function EP300 11%, Gain of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Progression-free survival rates (PFSR), Tumor progression rate (TPR) |
| Jallades et al., | 2017 | 46 | Ocular adnexal marginal zone lymphoma (OA-MZL), Splenic marginal zone lymphoma (SMZL) |
NOTCH2 17%, Gain of function NF1 16%, Gain of function TNFAIP3 15%, Loss of function TRAF3 13%, Loss of function ATM 13%, Loss of function |
Histology, Immunohistochemistry (IHC) | Overall survival (OS) |
| Qian et al., | 2020 | 24 | Splenic marginal zone lymphoma (SMZL) |
KLF2 18%, Loss of function NOTCH2 16%, Gain of function TP53 12%, Loss of function TNFAIP3 8%, Loss of function KMT2D 7%, Loss of function |
Histology, Molecular Biology Tests | 5 year overall survival rates (OSR) |
| Jangam et al., | 2020 | 16 | Ocular adnexal marginal zone lymphoma (OA-MZL) |
NOTCH2 19%, Gain of function TNFAIP3 15%, Loss of function TP53 11%, Loss of function TLBXR1 8%, Loss of function LRP1B 7%, Gain of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Tumor progression rate (TPR) |
| Johansson et al., | 2020 | 82 | Ocular adnexal marginal zone lymphoma (OA-MZL) |
TNFAIP3 22%, Loss of function NOTCH2 15%, Gain of function FAS 12%, Loss of function KMT2D 7%, Loss of function NOTCH1 5%, Gain of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Tumor progression rate (TPR) |
| Vela et al., | 2020 | 34 | Ocular adnexal marginal zone lymphoma (OA-MZL) |
PIK3CD 21%, Loss of function PTEN 16%, Gain of function TNFAIP3 10%, Loss of function NOTCH2 8%, Gain of function KLF2 6%, Loss of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Tumor progression rate (TPR) |
| Bonfiglio et al., | 2022 | 303 | Splenic marginal zone lymphoma (SMZL) |
NOTCH2 23%, Gain of function TNFAIP3 19%, Loss of function KLF2 15%, Loss of function SPEN 10%, Gain of function TRAF3 8%, Loss of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Progression-free survival rates (PFSR), Tumor progression rate (TPR) |
| Grau et al., | 2023 | 59 | Splenic marginal zone lymphoma (SMZL) |
NOTCH1 25%, Gain of function NOTCH2 16%, Gain of function CREBBP 13%, Loss of function TNFAIP3 9%, Loss of function EP300 6%, Gain of function |
Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Progression-free survival rates (PFSR) |
Genetic alterations in MZL
A synthesis of the selected studies revealed consistent genetic mutations in MZL, predominantly in the NOTCH2 and TNFAIP3 genes.
Prevalence of TNFAIP3 and NOTCH2 mutations
A detailed analysis of the TNFAIP3 and NOTCH2 mutations is summarized in Table 2. Within SMZL, mutations were notable in several studies: Pliva et al. found mutations in 19 out of 26 patients; Clipsson et al. in 38 out of 42; for NOTCH2, Parry et al. reported mutations in 43 out of 95, and Piava et al. in 17 out of 39. The main methodologies for these evaluations were Histology and Immunohistochemistry (IHC).
Table 2.
Comprehensive analysis of TNFAIP3 and NOTCH2 mutations in SMZL and OA-MZL across various studies
| Genes | MZL type | Studies | Number of mutated cases (MC) | Number of non-mutated cases (NMC) | Pathological examination | Prognostic outcomes |
|---|---|---|---|---|---|---|
| NOTCH2 | Splenic marginal zone lymphoma (SMZL) | Parry et al., | 43 | 52 | Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Progression-free survival rates (PFSR), Tumor progression rate (TPR) |
| Piva et al., | 22 | 17 | ||||
| Clipson et al., | 16 | 18 | ||||
| Campos-Martin et al., | 7 | 5 | ||||
| Jallades et al., | 6 | 5 | ||||
| Qian et al., | 6 | 4 | ||||
| Bonfiglio et al., | 22 | 18 | ||||
| Grau et al., | 12 | 11 | ||||
| TNFAIP3 | Splenic marginal zone lymphoma (SMZL) | Parry et al., | 52 | 47 | Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Progression-free survival rates (PFSR), Tumor progression rate (TPR) |
| Piva et al., | 26 | 19 | ||||
| Clipson et al., | 42 | 38 | ||||
| Campos-Martin et al., | 8 | 6 | ||||
| Jallades et al., | 5 | 5 | ||||
| Qian et al., | 4 | 5 | ||||
| Bonfiglio et al., | 20 | 18 | ||||
| Grau et al., | 10 | 8 | ||||
| NOTCH2 | Ocular adnexal marginal zone lymphoma (OA-MZL) | Jallades et al., | 5 | 4 | Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Tumor progression rate (TPR) |
| Jangam et al., | 4 | 5 | ||||
| Johansson et al., | 12 | 10 | ||||
| Vela et al., | 5 | 6 | ||||
| TNFAIP3 | Ocular adnexal marginal zone lymphoma (OA-MZL) | Jallades et al., | 4 | 4 | Histology, Immunohistochemistry (IHC) | 5 year overall survival rates (OSR), Tumor progression rate (TPR) |
| Jangam et al., | 3 | 5 | ||||
| Johansson et al., | 13 | 12 | ||||
| Vela et al., | 3 | 4 |
Pathological correlations
The relationship between pathological features and the prevalence of and TNFAIP3 mutations is presented in Table 3. NOTCH2 mutations were associated with specific cellular features: patients mainly had medium to large lymphocyte sizes, with 73.6% showing a high plasmacytoid differentiation rate and 66.7% having an increased centrocyte appearance rate. Conversely, those without NOTCH2 mutations primarily displayed small to medium-sized lymphocytes. TNFAIP3 mutations were correlated with 59.5% high plasmacytoid differentiation and 75.2% increased centrocyte appearances. Other markers, including BCL-2, CD43, CD21, and Ki-67, varied between the mutated and non-mutated groups, highlighting the mutations’ influence on pathological features.
Table 3.
Correlation between pathological features and the prevalence of NOTCH2 and TNFAIP3 mutations in MZL
| Pathological features | Patients with NOTCH2 mutation (SMZL: n = 134; OA-MZL: n = 26) | Patients without NOTCH2 mutation (SMZL: n = 130; OA-MZL: n = 25) | Patients with TNFAIP3 mutation (SMZL: n = 167; OA-MZL: n = 23) | Patients without TNFAIP3 mutation (SMZL: n = 146; OA-MZL: n = 25) |
|---|---|---|---|---|
| - Lymphocyte size | Medium to Large | Small to Medium | Medium to Large | Small to Medium |
| - Plasmacytoid differentiation rate | High (73.6%) | Moderate (35.7%) | High (69.5%) | Moderate (31.4%) |
| - Centrocyte appearance rate | Increased (66.7%) | Less frequent (23.5%) | Increased (75.2%) | Less frequent (30.1%) |
| - Tumor tissue morphology | Slightly disorganized | Relatively organized | Slightly disorganized | Relatively organized |
| - Extranodal Infiltration | High occurrence (67.4% with peripheral blood infiltration) | Low occurrence (32.5% with peripheral blood infiltration) | High occurrence (67.4% with peripheral blood infiltration) | Low occurrence (38.1% with peripheral blood infiltration) |
| - BCL-2 Positivity Rate | 84.5% | 49.7% | 76.3% | 55.3% |
| - CD43 Positivity Rate | 73.6% | 42.9% | 77.4% | 45.2% |
| - CD21 (interacting with follicular T cells) | 62.5% | 31.7% | 69.2% | 34.3% |
| - Ki-67 (proliferation index) | Higher (73.7%) | Lower (19.5%) | Higher (68.3%) | Lower (23.6%) |
Prognostic implications
In patients with SMZL and NOTCH2 mutations, we observed a significant difference in the 5-year overall survival rates (OSR) between mutated cases (MC) and non-mutated cases (NMC). The data in Fig. 2 reveals an SMD of -11.11 with a 95% confidence interval from − 13.39 to -8.84 (P < 0.01, I²: 70%). Moreover, the progression-free survival rates (PFSR) for these mutations, presented in Figure S1, show an SMD of -23.49 with a 95% confidence interval from − 28.85 to -18.14 (P < 0.01, I²: 73%). The tumor progression rate (TPR) data in Figure S2 indicates an SMD of 13.33 with a range of 10.54 to 16.12 (P < 0.01, I2: 50%).
Fig. 2.
Forest plot representing the difference in 5-year overall survival rates (OSR) between SMZL patients with and without NOTCH2 mutations
For SMZL patients with TNFAIP3 mutations, the 5-year OSR data in Fig. 3 reveals an SMD of -14.78 and a 95% confidence interval from − 18.01 to -11.56 (P < 0.01, I2: 78%). The PFSR data in Figure S3 indicates an SMD of -21.06 with a confidence interval from − 27.13 to -14.98 (P < 0.01, I2: 77%). The TPR data in Figure S4 reflects an SMD of 15.14 with a range from 13.21 to -17.07 (P < 0.01, I²: 89%).
Fig. 3.
Forest plot depicting the variance in 5-year OSR for SMZL patients based on the presence or absence of TNFAIP3 mutations
For ocular adnexa MZL (OA-MZL) patients with NOTCH2 mutations, the data from Fig. 4 highlights a significant difference in the 5-year OSR with an SMD of -23.40 and a confidence interval from − 28.87 to -17.93 (P < 0.01, I2: 70%). The TPR data presented in Figure S5 offers an SMD of 14.66 within the range of 9.30 to 20.01 (P < 0.05, I2: 55%).
Fig. 4.
Forest plot detailing the 5-year OSR differences in OA-MZL patients based on NOTCH2 mutation status
Lastly, in OA-MZL patients with TNFAIP3 mutations, the 5-year OSR data from Fig. 5 shows an SMD of -20.24 with a confidence interval from − 33.15 to -7.33 (P < 0.01, I2: 84%). The TPR data in Figure S6 presents an SMD of 21.81 with bounds from 15.98 to -27.64 (P < 0.05, I2: 80%).
Fig. 5.
Forest plot highlighting the difference in 5-year OSR for OA-MZL patients based on the TNFAIP3 mutation status
Publication bias
Funnel plots were employed to assess the potential publication bias concerning the 5-year overall survival rates (OSR) of mutated cases versus non-mutated cases. Figure S7 illustrates the funnel plot for NOTCH2 mutated cases (MC) compared to non-mutated cases (NMC) in SMZL patients. Similarly, Figure S8 showcases the funnel plot for TNFAIP3 mutated cases (MC) versus non-mutated cases (NMC) in OA-MZL patients. These plots further validate the robustness of our meta-analysis findings.
Discussion
MZL represents a spectrum of non-Hodgkin lymphomas with distinct clinical and genetic features. Our meta-analysis sought to elucidate the implications of genetic alterations on MZL prognosis, with a special emphasis on the NOTCH2 and TNFAIP3 mutations.
A clear pattern emerged from our analysis: genetic alterations in MZL, particularly mutations in NOTCH2 and TNFAIP3, significantly influence prognostic outcomes. The predominant presence of these mutations, especially in SMZL and OA-MZL patients, underscores their potential role in MZL pathogenesis and progression. Previous research aligns with these findings, wherein NOTCH2 and TNFAIP3 mutations were found to be integral to MZL evolution and aggressiveness [1].
The association between NOTCH2 mutations and specific cellular features adds a layer of complexity. Patients with these mutations predominantly exhibited medium to large lymphocyte sizes, whereas those without these mutations displayed smaller lymphocytes. Such correlations indicate that these mutations might play a role in dictating tumor microenvironments and cellular morphologies. This is consistent with studies suggesting that NOTCH signaling drives cellular differentiation and growth in various malignancies [19].
Our results highlight the tangible repercussions of these mutations on prognosis. SMZL patients with NOTCH2 mutations had markedly different survival rates and tumor progression compared to those without mutations. Similarly, TNFAIP3 mutations influenced survival and progression outcomes, echoing findings that mutations in this gene are associated with disrupted A20 protein function, leading to prolonged NF-κB signaling and subsequent tumor growth [20].
Another notable aspect is the variance in survival outcomes for SMZL and OA-MZL patients. The data suggests a more pronounced impact of these mutations in OA-MZL patients compared to SMZL patients. This disparity might be attributed to the underlying genetic and clinical heterogeneity between these MZL subtypes [21].
Our study underscores the pressing need for therapeutic strategies that target these specific genetic alterations. The consistent association of these mutations with poorer prognostic outcomes necessitates the development of therapies that either directly target the mutated genes or their downstream pathways [22]. For instance, NOTCH2 inhibitors could be explored for patients exhibiting NOTCH2 mutations. Similarly, targeted therapies against TNFAIP3 mutations might offer a promising avenue, given the significant role of TNFAIP3 in regulating inflammatory responses and apoptosis [23].
However, our study does have certain limitations. The presence of heterogeneity among included studies, as reflected in the I² values, warrants a cautious interpretation of our findings. While we strived for a comprehensive meta-analysis, the variability in study methodologies, patient populations, and treatments could introduce potential biases. Moreover, while NOTCH2 and TNFAIP3 were the predominant focus, MZL’s genetic landscape is vast, and the exploration of other genetic alterations could provide a more holistic understanding. In addition, TP53 is a tumor suppressor gene that plays a crucial role in cell cycle control, DNA repair, and apoptosis. When the TP53 gene is mutated, it may lose these normal regulatory functions, making cells more susceptible to cancerous changes and proliferation. The impact of TP53 mutation on the prognosis of MZL may include reduced survival rates, poor treatment response, increased risk of disease progression, and prognostic stratification. TP53 alteration could be an early marker of aggressive transformation or refractoriness which could be advised for evaluation at diagnosis in particular subset of non-Hodgkin lymphomas [24]. Although TP53 mutations have shown strong associations with poor prognosis in mantle cell lymphoma (MCL), studies specific to MZL are currently limited [25]. Thus, we have not included an in-depth discussion of TP53 in this manuscript due to the insufficient literature available for robust analysis. Given the potential prognostic significance of TP53 mutations in MZL, future studies with larger cohorts and comprehensive genomic analyses are warranted to elucidate its role. This could contribute to more refined prognostic models and tailored therapeutic strategies for MZL patients.
In conclusion, our meta-analysis confirms the profound impact of genetic alterations, especially NOTCH2 and TNFAIP3 mutations, on MZL prognosis. Their presence not only shapes the cellular landscape of the tumor but also dictates survival and progression outcomes. As the realm of precision medicine continues to expand, understanding these genetic nuances becomes paramount, guiding the development of targeted and effective therapeutic strategies for MZL patients.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
The authors are grateful to all participants in the present study.
Author contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xijing Li, Yang Lin and Licai An. The first draft of the manuscript was written by Xijing Li and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This study was not supported by any sponsor or funder.
Data availability
The data involved in the present study can be provided under reasonable request.
Declarations
Ethical statement and informed consent
Not applicable.
Consent to participate
Not applicable.
Consent to publish
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xijing Li and Yang Lin contributed equally to this work.
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Supplementary Materials
Data Availability Statement
The data involved in the present study can be provided under reasonable request.