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Meta-Analysis
. 2021 Jun 18:12:691557.
doi: 10.3389/fendo.2021.691557. eCollection 2021.

Prognostic Significance of Altered ATRX/DAXX Gene in Pancreatic Neuroendocrine Tumors: A Meta-Analysis

Fei Wang  1   2   3   4 , Xiaowu Xu  1   2   3   4 , Zeng Ye  1   2   3   4 , Yi Qin  1   2   3   4 , Xianjun Yu  1   2   3   4 , Shunrong Ji  1   2   3   4
Affiliations
Meta-Analysis

Prognostic Significance of Altered ATRX/DAXX Gene in Pancreatic Neuroendocrine Tumors: A Meta-Analysis

Fei Wang et al. Front Endocrinol (Lausanne). .

Abstract

Background: Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing recently has shown very frequent somatic mutations in the alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes in PanNETs. And the prognostic significance of altered ATRX/DAXX genes in PanNETs patients have been revealed in several reports. However, many of these include small sample size and hold controversial opinions. To increase statistical power, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of altered ATRX/DAXX genes mainly on overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) in PanNETs.

Methods: Eligible studies were identified and quality was assessed using multiple search strategies (last search May 2021). Data were collected from studies about prognostic significance of altered ATRX/DAXX in PanNETs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations.

Results: Fourteen studies involving 2313 patients treated for PanNETs were included. After evaluating for publication bias, disease-free survival and relapse-free survival was significantly shortened in patients with altered ATRX/DAXX gene, with combined HR 5.05 (95% confidence interval (CI): 1.58-16.20, P = 0.01) and 3.21 (95% confidence interval (CI): 1.44-7.16, P < 0.01) respectively. However, the combined data showed there were no difference between patients with altered ATRX/DAXX gene or not in overall survival, with a combined HR 0.71 (95% confidence interval (CI): 0.44-1.15, P = 0.23). We also performed a subgroup analysis with metastatic patients in overall survival, showing a combined HR 0.22 (95% confidence interval (CI): 0.11-0.48, P = 0.96). The small number of studies and paucity of multivariate analyses are the limitations of our study.

Conclusions: This is the first rigorous pooled analysis assessing ATRX/DAXX mutation as prognostic biomarkers in PanNETs. Patients with altered ATRX/DAXX gene would have poor DFS according to the combined data. And altered ATRX/DAXX genes in metastatic patients showed a trend towards improved overall survival, although the difference did not reach statistical significance.

Keywords: ATRX; DAXX; meta-analysis; pancreatic neuroendocrine tumors; prognosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flow chart of included articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Figure 2
Figure 2
(A) Forest plot showing the combined hazard ratio (HR) from studies for the association between ATRX/DAXX mutation and overall survival. Horizontal lines represent 95% confidence interval (CI). Each box represents the HR point estimate, and its area is proportional to the weight of the study, determined by inverse variance weighting. The diamond represents the overall summary estimate, with the 95% CI given by its width. (B) Funnel plot of standard error of assessing publication bias.
Figure 3
Figure 3
(A) Forest plot showing the combined hazard ratio (HR) from subgroup analysis for the association between ATRX/DAXX mutation with metastatic patients and overall survival. Horizontal lines represent 95% confidence interval (CI). Each box represents the HR point estimate, and its area is proportional to the weight of the study, determined by inverse variance weighting. The diamond represents the overall summary estimate, with the 95% CI given by its width. (B) Funnel plot of standard error of assessing publication bias.
Figure 4
Figure 4
(A) Forest plot showing the combined hazard ratio (HR) from studies for the association between ATRX/DAXX mutation and disease-free survival. Horizontal lines represent 95% confidence interval (CI). Each box represents the HR point estimate, and its area is proportional to the weight of the study, determined by inverse variance weighting. The diamond represents the overall summary estimate, with the 95% CI given by its width. (B) Funnel plot of standard error of assessing publication bias.
Figure 5
Figure 5
(A) Forest plot showing the combined hazard ratio (HR) from studies for the association between ATRX/DAXX mutation and relapse-free survival. Horizontal lines represent 95% confidence interval (CI). Each box represents the HR point estimate, and its area is proportional to the weight of the study, determined by inverse variance weighting. The diamond represents the overall summary estimate, with the 95% CI given by its width. (B) Funnel plot of standard error of assessing publication bias.
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