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

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.

Automated summary

This study is the first rigorous pooled analysis assessing ATRX/DAXX mutations as prognostic biomarkers in PanNETs. The results indicate that patients with altered ATRX/DAXX genes have poor DFS, while altered ATRX/DAXX genes in metastatic patients show a trend towards improved overall survival.