DAXX mutations as potential genomic markers of malignant evolution in small nonfunctioning pancreatic neuroendocrine tumors

Cives, Mauro; Partelli, Stefano; Palmirotta, Raffaele; Lovero, Domenica; Mandriani, Barbara; Quaresmini, Davide; Pellè, Eleonora; Andreasi, Valentina; Castelli, Paola; Strosberg, Jonathan R.; Zamboni, Giuseppe; Falconi, Massimo; Silvestris, Franco

doi:10.1038/s41598-019-55156-0

Cited by 28 publications

(27 citation statements)

References 21 publications

(36 reference statements)

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“…The same opinion was hold by Raj et al (17), Park et al (18) as well as Kim et al (19). However, others were in disagreement (10,11,(20)(21)(22). In their report, the mutations found in the ATRX/DAXX genes was significantly correlated with a shortened survival time.…”

Section: Introductionmentioning

confidence: 58%

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

Wang

Zeng

et al. 2021

Front. Endocrinol.

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BackgroundPancreatic 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.MethodsEligible 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.ResultsFourteen 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.ConclusionsThis 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.

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Section: Introductionmentioning

confidence: 58%

“…A total of 14 studies with 2313 patients (range from 16-561 per study) were assessed in this meta-analysis (1,10,11,(17)(18)(19)(20)(21)(22)(24)(25)(26)(27)(28). Studies included were published from 2011 to 2021.…”

Section: Study Characteristicsmentioning

confidence: 99%

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

Wang

Zeng

et al. 2021

Front. Endocrinol.

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“…Another study compared the mutational profiles of PanNEN that were larger than 2 cm (n = 29) or smaller than 2 cm (n = 27). Herein, it was observed that there was a significantly higher mutational burden in tumours >2 cm, the prevalence of DAXX mutations was borderline significantly higher in larger tumours, and DAXX mutations were associated with increased histological grade, relapse after surgery and reduced disease-free survival (Cives et al 2019a).…”

Section: Pancreatic Neuroendocrine Neoplasmsmentioning

confidence: 90%

Using genetics to inform the pharmacological targeting of neuroendocrine neoplasms

Clift

Frilling

2020

Endocrine-Related Cancer

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Neuroendocrine neoplasms (NEN) are a class of tumours heterogeneous in terms of their anatomical sites of origin and clinical behaviour. Outdated perspectives of indolence have been superseded by appreciation for their myriad clinical challenges, such as the high rates of regional and distant metastases at initial diagnosis, lack of clarity on optimal treatment strategies/sequencing, and incompletely elucidated genetic/other pathophysiological drivers. The first randomised controlled trials in this arena were published approximately a decade ago – since then, increased understanding of the genetic drivers and signalling pathway perturbations in these tumours have suggested promise for precision therapy influenced by an individual tumour’s molecular sub-type, but this is yet to be realised for manifold reasons. In this article, the authors review the genetic landscapes as currently understood for selected forms of NEN and discuss the current and developing evidence to support the use of genetic information to influence therapy. They provide a critical assessment of the potential limitations of using such approaches, and also posit avenues for future developments in this arena.

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“…ALT and loss of DAXX/ATRX are associated with decreased DFS (Marinoni et al 2014, Pipinikas et al 2015, Singhi et al 2017, Chou et al 2018, Roy et al 2018, Cives et al 2019, ATRX loss is associated with poorer OS (Chou et al 2018) and DAXX/ ATRX loss is associated with shorted DSS (Marinoni et al 2014). ALT associated with distant metastases in NF-pNETs <3 cm (Pea et al 2020).…”

Section: Prognostic Factor Evidence In Men1-related Nf-pnets Evidence In Sporadic Nf-pnetsmentioning

confidence: 99%

“…Several retrospective cohort studies have assessed the prognostic value of DAXX/ATRX loss and/or ALT positivity in sporadic surgically resected pNETs (nonfunctioning 75-100%) (Jiao et al 2011, Dogeas et al 2014, Marinoni et al 2014, Pipinikas et al 2015, Park et al 2017, Singhi et al 2017, Chou et al 2018, Pea et al 2020, Roy et al 2018, Cives et al 2019, Uemura et al 2019). All but one study (Park et al 2017) found that ALT and/or DAXX/ ATRX loss (IHC) was associated with decreased relapse-, recurrence-or progression-free survival (Marinoni et al 2014, Pipinikas et al 2015, Singhi et al 2017, Chou et al 2018, Roy et al 2018, Cives et al 2019). One study (Chou et al 2018) also found ATRX loss to be associated with poorer OS and in another study (Marinoni et al 2014) DAXX/ATRX loss was associated with shorter DSS.…”

Section: Imaging-related Characteristicsmentioning

confidence: 99%

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature

Sadowski

Pieterman

Perrier

et al. 2020

Endocrine-Related Cancer

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Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.

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DAXX mutations as potential genomic markers of malignant evolution in small nonfunctioning pancreatic neuroendocrine tumors

Cited by 28 publications

References 21 publications

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

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

Using genetics to inform the pharmacological targeting of neuroendocrine neoplasms

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature

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