Extensive acrochordons and pancreatic islet‐cell tumors in tuberous sclerosis associated with <i>TSC2</i> mutations

Merritt, J. Lawrence; Davis, Dawn M.; Pittelkow, Mark R.; Babovic‐Vuksanovic, Dusica

doi:10.1002/ajmg.a.31351

Cited by 38 publications

(20 citation statements)

References 15 publications

(12 reference statements)

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“…These regulatory genes include, most notably, phosphatase and tensin homolog (PTEN) [54,55], the tuberous sclerosis complex 2 gene (TSC2) [56,57,58] and, possibly, neurofibromatosis type 1 [59,60]. In a recent gene expression profiling study using a large panel of pancreatic NET, PTEN and TSC2 were downregulated in most primary tumors examined [61].…”

Section: Molecular Targets In Pancreatic Netmentioning

confidence: 99%

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

2011

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Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.

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Section: Molecular Targets In Pancreatic Netmentioning

confidence: 99%

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

2011

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“…LKB1 also affects tumor angiogenesis, invasiveness and metastasis (Zhuang et al, 2006). Mutations of TSC2 lead to tuberous sclerosis syndrome, which is is an autosomal dominant disorder characterized by widespread hamartosis and TSC2 mutations may be a risk factor for developing tumors such as pancreatic islet-cell tumors and renal cell carcinoma (Sampson and Harris, 1994;Merritt et al, 2006;Yeung et al, 1994). Loss of TSC2 is also associated with tumor metastasis and development (PachecoRodriguez et al, 2007).…”

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confidence: 99%

Role of mTOR in anticancer drug resistance: Perspectives for improved drug treatment

Jiang

Liu

2008

Drug Resistance Updates

225

181

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The mammalian target of rapamycin (mTOR) pathway plays a central role in regulating protein synthesis, ribosomal protein translation, and cap-dependent translation. Deregulations in mTOR signaling are frequently associated with tumorigenesis, angiogenesis, tumor growth and metastasis. This review highlights the role of the mTOR in anticancer drug resistance. We discuss the network of signaling pathways in which the mTOR kinase is involved, including the structure and activation of the mTOR complex and the pathways upstream and downstream of mTOR as well as other molecular interactions of mTOR. Major upstream signaling components in control of mTOR activity are PI3K/PTEN/AKT and Ras/Raf/MEK/ERK pathways. We discuss the central role of mTOR in mediating the translation of mRNAs of proteins related to cell cycle progression, those involved in cell survival such as c-myc, hypoxia inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF), cyclin A, cyclin dependent kinases (cdk1/2), cdk inhibitors (p21 Cip1 and p27 Kip1 ), retinoblastoma (Rb) protein, and RNA polymerases I and III. We then discuss the potential therapeutic opportunities for using mTOR inhibitors rapamycin, CCI-779, RAD001, and AP-23573 in cancer therapy as single agents or in combinations to reverse drug resistance.

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“…In another TSC patient, extensive lichenified hyperpigmented plagues suggesting a paraneoplastic process were thought to be related to a pancreatic islet cell neoplasm (weakly staining for glucagon on immunohistochemistry); in this case analysis sequencing of the TSC2 gene showed a novel 1 bp insertion at position 45-46, leading to a frame shift (Merritt et al 2006). There are two further case reports demonstrating malignant pancreatic tumours in TSC patients , Francalanci et al 2003.…”

Section: Non-functioning Islet Cell Tumourmentioning

confidence: 68%

Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review

Dworakowska¹,

Grossman²

2009

Endocrine-Related Cancer

109

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Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs. It is caused by mutations of two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode for hamartin and tuberin respectively. The interaction between these two proteins, the tuberin-hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation. TSC may affect skin, central nervous system, kidneys, heart, eyes, blood vessels, lung, bone and gastrointestinal tract. Small series and case reports have documented that in tuberous sclerosis patients many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid and other neuroendocrine tissue. There have been scattered reports of the involvement of such tissue in the pathological process of TSC, but no systematic review as to whether this is a true association. We have therefore systematically assessed all available published literature in this area. We conclude that there may be an association with pituitary and parathyroid tumours, and two recent descriptions of Cushing's disease are especially intriguing. However, the evidence seems more firm in the case of islet cell tumours, particularly insulinomas. As these latter may cause changes in mental state that may be confused with the cerebral manifestations of TSC per se, it is particularly important for physicians working with these patients to be aware of the putative and indeed likely association.

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Extensive acrochordons and pancreatic islet‐cell tumors in tuberous sclerosis associated with TSC2 mutations

Cited by 38 publications

References 15 publications

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

Role of mTOR in anticancer drug resistance: Perspectives for improved drug treatment

Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review

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