DAXX
 /
 ATRX
 ,
 MEN1
 , and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors

Jiao, Yuchen; Shi, Chanjuan; Edil, Barish H.; Wilde, Roeland F. de; Klimstra, David S.; Maitra, Anirban; Schulick, Richard D.; Tang, Laura H.; Wolfgang, Christopher L.; Choti, Michael A.; Velculescu, Victor E.; Díaz, Luis A.; Vogelstein, Bert; Kinzler, Kenneth W.; Hruban, Ralph H.; Papadopoulos, Nickolas

doi:10.1126/science.1200609

Cited by 1,546 publications

(1,547 citation statements)

References 26 publications

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“…Mutations in ATRX are common in various gliomas [37,38] and pancreatic neuroendocrine tumours [23,39]. The effect of ATRX mutation on prognosis is variable; several studies found an enhanced survival with ATRX mutation in some tumour types [39] but others report a worse prognosis [23,24].…”

Section: Be Howitt Et Almentioning

confidence: 99%

Targeted genomic analysis of Müllerian adenosarcoma

Howitt

Sholl

Cin

et al. 2014

The Journal of Pathology

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Müllerian adenosarcoma (MA) is a rare mixed mesenchymal tumour of the female genital tract, composed of malignant stroma and benign-appearing epithelium. Sarcomatous overgrowth (SO) is the only established histological variable associated with higher stage and shorter survival. Specific molecular or immunohistochemistry (IHC) tools for the diagnosis of MA are lacking. Our goal was to study genomic mutations and copy number variations (CNVs) in MA to understand better its pathobiology, and develop specific diagnostic and prognostic tools. DNA was extracted from 20 samples of MA from 18 subjects (12 without SO and 6 with SO), including two in which areas of both typical MA histology and SO were independently tested. Samples were analysed using a targeted next-generation sequencing assay interrogating exonic sequences of 275 cancer genes for mutations and CNVs as well as 91 introns across 30 genes for cancer-associated rearrangements. The mean number of mutations in MA with SO (mean 9.7; range 3-14) did not differ significantly from that in MA without SO (mean 9.6; range 5-16). MA with SO had significantly higher mean numbers of gene-level CNVs (24.6) compared to MA without SO (5; p = 0.0002). The most frequent amplification involved MDM2 and CDK4 (5/18; 28%), accompanied by focal CDK4 and MDM2 and diffuse HMGA2 expression using immunohistochemistry. MYBL1 amplification was seen in 4/18 (22%), predominantly in SO. Alterations in PIK3CA/AKT/PTEN pathway members were seen in 13/18 (72%). Notably, TP53 mutations were uncommon, present in only two cases with SO. Three out of 18 (17%) had mutations in ATRX, all associated with SO. No chromosomal rearrangements were identified. We have identified a number of recurrent genomic alterations in MA, including some associated with SO. Although further investigation of these findings is needed, confirmation of one or more may lead to new mechanistic insights and novel markers for this often difficult-to-diagnose tumour.

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Section: Be Howitt Et Almentioning

confidence: 99%

Targeted genomic analysis of Müllerian adenosarcoma

Howitt

Sholl

Cin

et al. 2014

The Journal of Pathology

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“…25 Although the crucial role of mTOR seems to be mainly confined in the subgroup of pancreatic NETs (in fact about the 14% of these last present mutations in genes in the mTOR pathway). 26,27 The positive recent data from the RADIANT-4 trial 12 based on the use of mTOR targeting agent (everolimus) supported the leading role of mTOR axis in NETs not only in is pancreatic but also in lung or gastrointestinal tumors. The angiogenesis process along with one of its "driver" such as the vascular endothelial growth factor (VEGF) play also an important role in NETs progression.…”

Section: Discussionmentioning

confidence: 99%

Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

Roviello

Zanotti

Venturini

et al. 2016

Cancer Biology & Therapy

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Background: Several randomized phase III trials in neuroendocrine tumors (NETs) showed the clinical role of new targeted agents and their impact on tumor response and outcome of whose patients affected by advanced NET. In this study, we summarize the available clinical data related to clinical efficacy of targeted therapies in the treatment of advanced NETs. Methods: A meta-analysis of randomized studies in accordance with the PRISMA guidelines was performed after searching the databases of PubMed, the Cochrane Library, and the ASCO University Meeting for relevant publications. Results: One thousand 9 hundred and 8 cases were included in the meta-analysis; among these, 1012 were in the experimental arm and 896 were in the control arm. The pooled analysis of the use of target agents in NETs revealed significantly increased of progression free survival compared to control group (hazard ratio D 0.59, 95% CI:0.42-0.84; P D 0.003). Subgroup analysis of patients according to tumor site showed a difference in favor of pancreatic neuroendocrine tumors. Moreover, targeted therapies improved the overall survival (hazard ratio D 0.79, 95%CI: 0.63-0.98; P D 0.03), and response rate (hazard ratio D 3.33, 95% CI 2.02-5.49; P < 0.00001) in all types of NETs. Conclusion: Our analysis supports the routine use of targeted agents for treatment of neuroendocrine tumors with particular regards to the pancreatic neuroendocrine tumors.

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“…In a phase III clinical trial, patients treated with everolimus showed an improved median progression-free survival of 11 months compared to the placebo group (4.6 months) [97]. Although these results are encouraging, mutations of the mTOR pathways are present in only 16 % of pNETs, making everolimus beneficial for only a minority of patients [4].…”

Section: Targeted Molecular Therapymentioning

confidence: 99%

“…Commonly identified, in order of frequency, are mutations of MEN1 (44 %), DAXX (25 %), ARTX (18 %), and genes of the mTOR pathway (16 %) [4]. Characteristic is the almost complete absence of the KRAS mutation which is distinctly different than pancreas adenocarcinoma where KRAS mutations are common.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Neuroendocrine Tumors: an Update

2015

Self Cite

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Pancreatic neuroendocrine tumors (pNETs) are rare and comprise only 1-2 % of all pancreatic neoplastic disease. Although the majority of these tumors are sporadic (90 %), pNETs can arise in the setting of several different hereditary genetic syndromes, most commonly multiple endocrine neoplasia type 1 (MEN1). The presentation of pNETs varies widely, with over 60 % having malignant distant disease at the time of initial diagnosis involving the liver or other distant sites. Functioning pNETs represent approximately 10 % of all pNETs, secrete a variety of peptide hormones, and are responsible for several clinical syndromes caused by profound hormonal derangement. Surgery remains the cornerstone of therapy and the only curative approach. It should be pursued for localized disease and for metastatic lesions amenable to resection. Multimodality therapies, including liver-directed therapies and medical therapy, are gaining increasing favor in the treatment of advanced pNETs. Their utility is multifold and spans from ameliorating symptoms of hormonal excess (functional pNETs) to controlling the local and systemic disease burden (non-functional pNETs). The recent introduction of target molecular therapy has promising results especially for the treatment of progressive well-differentiated G1/G2 tumor. In this review, we summarize the current knowledge and give an update on recent advancements made in the therapeutic strategies for pNETs.

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DAXX / ATRX , MEN1 , and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors

Cited by 1,546 publications

References 26 publications

Targeted genomic analysis of Müllerian adenosarcoma

Targeted genomic analysis of Müllerian adenosarcoma

Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

Pancreatic Neuroendocrine Tumors: an Update

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