The der(1;7)(q10;p10) defining a distinct profile from −7/del(7q) in myelodysplastic syndromes: A systematic review and meta‐analysis

Abstract Background and Objective Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by ineffective hematopoiesis due to stem cell abnormalities. Monosomy 7q aberrations are a common cytogenetic abnormality in MDS. Specifically, an unbalanced translocation der(1;7)(q10;p10) [der(1;7)] has been identified in MDS patients, which is a monosomy 7q aberration variant like −7/del(7q). However, knowledge of der(1;7)'s features remains limited. Existing studies have compared the clinical and genetic characteristics of der(1;7) to those of −7/del(7q) but yielded inconsistent findings. Accordingly, we conducted meta‐analyses comparing der(1;7) to −7/del(7q). Methods Publications were searched from the following databases up to January 10, 2023: Pubmed, Web of Science, Embase, Cochrane, and ClinicalTrials.gov. Eligible studies were assessed for risks of bias. Relevant data were extracted from included studies and analyzed using random‐effects models. Publication bias was evaluated and sensitivity analyses were performed. Results The comparative meta‐analyses included 405 MDS patients with der(1;7) from nine studies. The analysis revealed that der(1;7) was associated with a greater male preponderance (86.1% vs. 68.3%, Odds Ratios (ORs) 2.007, p < 0.01) than −7/del(7q), lower platelets counts compared to del(7q), higher hemoglobin levels than −7, lower absolute neutrophil counts, and higher percentage of patients with non‐excess blasts (66.9% vs. 41.3%, ORs 2.374, p = 0.01) in comparison with −7/del(7q). The der(1;7) existed more as a sole karyotype aberration (55.6% vs. 37.0%, ORs 2.902, p = 0.02), co‐occurred more often with +8 (22.7% vs. 4.2%, ORs 5.714, p = 0.04) whereas less −5/del(5q) (1.5% vs. 41.3%, ORs 0.040, p < 0.01) and complex karyotype (7.3% vs. 54.8%, OR 0.085, p < 0.01). The der(1;7) was associated with higher frequencies of RUNX1 (40.8% vs. 12.3%, ORs 4.764, p < 0.01), ETNK1 (28.1% vs. 2.5%, ORs 42.106, p < 0.01) and EZH2 (24.8% vs. 6.9%, ORs 3.767, p = 0.02) mutations, but less TP53 mutation (2.4% vs. 45.3%, ORs 0.043, p < 0.01). Moreover, der(1;7) patients had longer time to progression (Hazard Ratios (HRs) 0.331, p = 0.02), better overall survival (OS) than −7 patients (HRs 0.557, p < 0.01), but similar OS with del(7q) patients (HRs 0.837, p = 0.37). Conclusion The findings revealed distinct clinical, cytogenetic, and molecular characteristics distinguishing der(1;7) from −7/del(7q), indicating der(1;7) defines a unique subtype within MDS with monosomy 7q. These findings support classifying der(1;7) as a separate MDS entity in future.

This study conducted a systematic review and metaanalysis to summarize available data on: gender and age distribution, peripheral blood counts, bone marrow blast percentage, and spectrum of co-occurring aberrations and mutations, prognosis between MDS with der(1;7) versus −7/ del(7q).The aim was to overcome the limitations of prior smaller studies by analyzing pooled data on important clinical characteristics of MDS with der(1;7).This would assess differences between the two cytogenetic subgroups and help elucidate whether der(1;7) represents a unique clinical entity.

| Study registration and search strategy
This systematic review and meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42023387515).The methodology followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement guidelines. 22The following databases were searched for publications up to January 10, 2023: PubMed, Web of Science, Embase, Cochrane, and Clini calTr ials.gov.The search terms were liberalized as the followings to capture all relevant studies: (der(1;7) OR der(1;7)(q10;p10) OR der(7)t(1;7)(q10;p10)) AND (MDS OR (myelodysplastic syndromes) OR (myelodysplastic neoplasms)).Further details are provided in Supplementary Search Strategies.

Conclusion:
The findings revealed distinct clinical, cytogenetic, and molecular characteristics distinguishing der(1;7) from −7/del(7q), indicating der(1;7) defines a unique subtype within MDS with monosomy 7q.These findings support classifying der(1;7) as a separate MDS entity in future.to calculate Odd Ratio (OR) for dichotomous variables or Hazard Ratio (HR) for survival with 95% confidence intervals (95% CI) for comparative analyses, and studies providing adequate statistical information on clinical features of der(1;7) for single-arm meta-analyses.
Studies were excluded if they were case reports or lacked sufficient quantitative data to enable comparative analyses or single-arm meta-analyses.Two authors independently screened studies for eligibility and resolved discrepancies by discussion.

| Data extraction and risk of bias assessment
Data were extracted on author, journal/year, region, histopathology, cohort size and incidence of der(1;7), gender, age, percentage of t-MDS/AML, peripheral blood counts, bone marrow blast percentage at diagnosis, frequencies of cytogenetic aberrations and mutations, and survival data for der(1;7) and −7/del(7q) MDS.Engauge Digitizer was applied to extract data from Kaplan-Meier curves to calculate HR and 95% CI using Tierney's method. 23The Newcastle-Ottawa Scale (NOS) was used to assess study quality and risk of bias, with scores between 8 and 9 points indicating high quality with a low risk of bias, scores between 5 and 7 points indicating intermediate quality with an intermediate risk of bias, and scores less than 5 points indicating low quality with a high risk of bias. 24

| Statistical analysis
Comparative and single-arm meta-analyses were performed using either the Onlinemeta v1.0 web tool (https:// smuon co.shiny apps.io/ Onlin emeta/ ) or the "meta" and "metamedian" R packages. 25,26Random effects models were utilized to calculate pooled estimates that account for within-study random error and between-study variation. 27A p-value <0.05 indicated statistical significance.Cochrane χ 2 test and I 2 statistics were used to evaluate heterogeneity, with I 2 < 25%, 25%-50%, and >50% indicating low, moderate, and high heterogeneity, respectively. 28ublication bias was assessed using funnel plots, Egger's, and Begg's tests. 29Sensitivity analyses investigated the impact of removing individual studies on the pooled HRs for overall survival (OS) to evaluate the stability of the meta-analysis.

| Literature search
Two investigators independently searched databases, identifying 140 articles.After removing duplicates, 112 titles/abstracts were screened, excluding 57 unrelated studies.Of the remaining 55 articles assessed for eligibility, 12 studies were finally included in the quantitative synthesis.The search flow is shown in Figure 1.

F I G U R E 1
The flow diagram shows the selection process used to identify relevant studies for the review and metaanalysis.

| Study characteristics and risk of bias assessment
The characteristics of the 12 eligible studies are shown in Table 1.The number of der(1;7) MDS patients ranged from 6 to 95 across the studies. All were retrospective cohorts: 9 reported in articles, 2 in letters, 7,9 1 in abstract.13,20 Of the 9 studies reported in articles, 3 had low and 6 intermediate risk of bias according to NOS (Table S1).The 2 from letters 7,9 and 1 from an abstract 13 could not be assessed for NOS scores. Howver, these three studies all involved large cohort sizes and provided complete relevant clinical data.Due to these characteristics suggesting low or intermediate risk of bias, they were also included in the analytical investigations. Nostudies were determined to exhibit a high risk of bias in the analyses.

T A B L E 1
The characteristic of der(1;7) MDS studies included in the meta-analysis.The der(1;7) incidence was 73/763 (0.80%) in the Japanese MDS cohort and 4/944 (0.42%) in the German MDS cohort. f The der(1;7) incidence was 13/1620 (0.80%) in Children/Adolescents primary MDS cohort enrolled in the European Working Group of MDS in Childhood registries.

F I G U R E 2
The pooled Odds Ratios (ORs) for males and MDS with low blasts in der(1;7) patients versus − 7/del(7q) patients.(A) The forest plot shows the pooled ORs for males.(B) The forest plot shows the pooled OR for MDS with low blasts in MDS patients with der(1;7) versus with −7/del(7q).The pooled ORs and their 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel method with a random-effects model.The size of each square represents the weight of that study in the metaanalysis.The vertical dashed line shows the pooled ORs.And the vertical solid line represents an OR of 1.The diamond represents the pooled ORs and 95% CI.If they differ from 1, the difference is considered statistically significant.
a Data presented as mean (95% confidence interval) in Slovak et al while median (range) for other studies.

| Sensitivity analysis and publication bias analysis
A sensitivity analysis was conducted to verify the robustness of the meta-analysis findings on OS difference between der(1;7) with −7 and der(1;7) with del(7q).Excluding any single study had little effect on the pooled results, indicating the stability of the findings (Figure 5).The funnel plots for OS appeared approximately symmetric, suggesting no substantial publication bias (Figure S14).Furthermore, Egger's test and Begg's test revealed no evidence of publication bias for all the comparative meta-analyses (Table S2).additional abnormal karyotypes and their corresponding clinical phenotypes have been identified in MDS patients. 34,35The −7/del(7q) and der(1;7) abnormalities are both characterized by loss of 7q.The −7/del(7q) abnormality is relatively common in MDS and is associated with increased myeloblasts and poor prognosis, 3 while der(1;7) is less common and its phenotypes in MDS are not well summarized.Here, through meta-analysis, we identified a distinct clinical and genetic profile of MDS patients with der(1;7) compared to patients with −7/del(7q).The der(1;7) is characterized by a greater male preponderance, marked thrombocytopenia, higher HB, lower ANC, and lower blasts in MDS, with more sole aberration existence and co-occurrence of +8 in karyotype, and with higher frequencies for RUNX1, ETNK1, and EZH2 mutations.In contrast, the der(1;7) co-occurred infrequently with −5/ del(5q), CK, and TP53 mutations.Additionally, der(1;7) transformed to AML more slowly than −7 or del(7q) patients, showed longer OS compared with −7 patients, and had a similar OS with del(7q) patients.Our findings support categorizing der(1;7) as a unique entity within the group of MDS with monosomy 7q.

| DISCUSSION
Persistent cytopenia in one or more peripheral blood cell lineages is a key diagnostic criterion for MDS, 1 and our analysis demonstrated significant differences in blood counts among patients with der(1;7), −7, and del(7q).Studies included in our meta-analysis indicated that marked thrombocytopenia and coexisting anemia of varying severity were prominent clinical features in MDS with der(1;7).The meta-analysis also further revealed that patients with der(1;7) had significantly lower platelet counts compared to patients with del(7q) and higher hemoglobin levels compared to patients with −7.The study by Hussain et al. showed a similar trend that corroborated our findings. 21it.Absolute neutrophil counts were compared in only two studies.Therefore, to strengthen our analysis, we additionally included raw data from Bernard et al.'s cohort. 20With this extra data, our meta-analysis found that median absolute neutrophil counts were decreased in patients with der(1;7) and even lower compared to patients with −7/del(7q).RNA sequencing also suggested innate immunity pathways were more downregulated in der(1;7) patients versus −7/del(7q) and other karyotypes. 7,36These factors may partly explain increased odds of infections in der(1;7) cases. 36ur analysis revealed distinct cytogenetic and mutational profiles, and several findings provide evidence suggesting that der(1;7) represent an initiating or early clone in MDS.First, in nearly half of patients with der(1;7) at diagnosis, der(1;7) exhibited as the sole chromosomal abnormality, without other chromosomal aberrations.Second, three sole der(1;7) MDS cases even lacked common somatic mutations of MDS, 20,37 suggesting der(1;7) can be an initiating clone independent from other drivers of MDS.Third, we found that patients with der(1;7) had high frequencies of +8, and karyotype analysis demonstrated that +8 arose as a subclone from the original der(1;7) clone in some cases, 12 indicating that der(1;7) occurs earlier.EZH2, located at 7q36.1, was mutated more commonly in der(1;7) patients, and its mutations were also likely acquired later after the major der(1;7) clones based on mutation burden. 13hrombocytopenia in der(1;7) patients may be partially due to transcription factor dysregulation.During normal hematopoiesis, GATA1/2 interacts with FOG-1 to regulate early megakaryopoiesis. 38RUNX1 bifurcates the erythroid and megakaryocytic lineages, inhibits erythropoiesis while favors megakaryopoiesis, 39 and is also crucial for megakaryocyte terminal maturation. 40However, a study found hypermethylation of enhancer regions associated with GATA1-3 and RUNX1 binding sites in patients with der(1;7), 37 indicating dysregulation of these transcription factors at the epigenetic level.Concurrently, our metaanalysis confirmed a high frequency of RUNX1 mutations in patients with der(1;7).Both the epigenetic changes and RUNX1 mutations likely result in abnormal RUNX1 regulation in der(1;7) MDS, potentially influencing normal megakaryocyte development.
The study also revealed other significant differences in co-occurring genetic alterations between patients with der(1;7) and − 7/del(7q).ETNK1 mutations were enriched in der(1;7) patients, and their combinations may be potentially associated with MDS with eosinophilia, 13 warranting further research into this specific phenotype.In contrast, TP53 mutations, complex karyotype, and − 5/del(5q) abnormalities indicative of poorer prognosis in MDS with monosomy 7q, 41 were more frequent in patients with −7/ del(7q) while less frequent in patients with der(1;7).
In contrast to patients with −7/del(7q) who tend to progress to advanced MDS, 3,10,42 we found patients with der(1;7) had lower myeloblasts and slower transformation to AML.We also found that der(1;7) patients exhibited longer OS compared to −7/del(7q) patients, though with high heterogeneity.Our subgroup analysis reduced the heterogeneity and further clarified that der(1;7) patients had longer OS than −7 patients but similar survival as del(7q) patients in MDS.Sensitivity analysis confirmed the stability of this conclusion.
Notably, two studies yielded inconsistent results regarding the prognosis of patients with sole der(1;7) compared to those with sole −7. 10,21One suggested no difference in OS while the other showed longer OS for sole der(1;7).The meta-analysis of the two studies using different statistical model also showed inconsistent findings.The randomeffects model suggested a favorable but insignificant trend for sole der(1;7), while the fixed-effects model showed better OS for sole der(1;7).This inconsistency may due to the limited number of studies and the wider confidence intervals with random effects models. 27More relevant studies are needed to address differences in OS between sole der(1;7) and sole −7 in MDS.Considering the survival characteristics of −7 may be similar to those of −7/ del(7q), as −7 accounted for around 80% of −7/del(7q), 43 we included another study finding that sole der(1;7) had significantly longer OS and relapse time after transplantation than sole −7/del(7q). 31Combining data from the three studies, both fixed and random-effects models corroborate better prognosis for sole der(1;7) compared to sole −7.
This study has some limitations.First, the inclusion of only retrospective cohort studies introduces potential for selection bias, information bias, and confounding.Second, some studies did not adjust for potential confounders like age, sex, and disease risk in outcome analyses.Prognostic differences may be influenced by these factors.Third, two studies reported that der(1;7) patients could benefit more from transplantation with longer relapse time and improved survival, 19,31 however, the limited research precluded further subgroup analyses by specific treatment regimens.Studies focusing on response to specific therapies are further warranted.
To our knowledge, this is the first meta-analysis comparing the clinical and genetic characteristics of der(1;7) versus −7/del(7q).The study primarily found that der(1;7) was associated with a greater male preponderance, lower blasts, lower platelet counts than del(7q), higher hemoglobin than −7.Our study highlighted differences in cytogenetic abnormalities and mutations between the two groups.Moreover, der(1;7) also exhibited a longer time to AML progression, improved OS versus −7, and similar OS as del(7q) in MDS.In summary, this study resolved inconsistencies in previous studies by analyzing pooled data and identified key clinical characteristics that differentiate MDS patients with der(1;7) from those with −7/ del(7q).Our findings provide preliminary evidence to consider classifying der(1;7) as a distinct MDS subtype in the future.

F I G U R E 3
The cytogenetic and mutational profiles of der(1;7) patients and the pooled Odds Ratios (ORs) for co-lesions in der(1;7) versus − 7/del(7q) patients.(A) The pooled frequencies of co-occurring cytogenetic aberrations in der(1;7) patients.(B) The pooled ORs for sole chromosomal aberration, +8, complex karyotype and − 5/del(5q) in der(1;7) versus −7/del(7q) patients.(C) The pooled mutation frequencies in der(1;7) patients.(D) The pooled ORs for RUNX1, ETNK1, EZH2, TP53 and RAS pathway gene mutation in der(1;7) versus −7/del(7q) patients.RAS pathway genes include CBL, KRAS, NRAS, NF1 and PTPN11.The pooled frequencies were calculated using singlearm meta-analysis with an inverse variance random effects model.The pooled ORs were calculated using Mantel-Haenszel random effects meta-analysis.The dot represents the pooled ORs, and the error bar represents 95% confidence interval.The x-axis is on a log scale.The vertical dashed line represents an OR of 1.A p-value <0.05 is considered statistically significant.
Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and high genetic heterogeneity.In the 2022 WHO classification of MDS, 33 MDS-5q, MDS-SF3B1, and MDS-biTP53 have been classified as distinct subtypes based on their specific genetic features and associated clinical characteristics.Recently, more F I G U R E 4 Better Overall Survival (OS) for der(1;7) versus − 7 and similar OS for der(1;7) and del(7q) patients.(A) The forest plot shows the Hazard Ratios (HRs) of OS in patients with der(1;7) versus −7 (B) The forest plot shows the HRs of OS in patients with der(1;7) versus del(7q).The pooled HRs were calculated using the inverse variance method with a random effects model.The diamond represents the pooled HRs and 95% CI.And the vertical solid line represents a HR of 1.If the pooled HRs and its 95% confidence interval (95% CI) are <1, indicating a lower risk of death for der(1;7) patients.If the pooled HRs and 95% CI crosses 1, indicating no significant difference in OS.F I G U R E 5 Sensitivity analyses evaluating the stability of the results.(A) The sensitivity analysis of the pooled Hazard Ratios (HRs) for overall survival (OS) in der(1;7) versus −7.(B) The sensitivity analysis of the pooled HRs for OS in der(1;7) versus del(7q).For the sensitivity analysis, the pooled HRs and 95% confidence interval of OS were recalculated after excluding each study individually.
at diagnosis.