Pancreatic tumors in children and young adults with tuberous sclerosis complex

Koc, Gonca; Sugimoto, Sam; Kuperman, Rachel; Kammen, Bamidele F.; Karakas, Serdar

doi:10.1007/s00247-016-3701-0

Cited by 35 publications

(28 citation statements)

References 26 publications

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“…9 and 16, respectively), is a highpenetrance autosomal dominant syndrome associated with benign hamartomas, cognitive impairment and epilepsy. Development of PanNETs is less frequent, ranging between 1.8 and 9% (Anlauf et al 2007, Larson et al 2012, Koc et al 2017. These are mainly due to germline TSC2 mutations, consistent with the observation that sporadic PanNETs harbour recurrent somatic mutations mainly in TSC2 (Jiao et al 2011).…”

Section: Tuberous Sclerosis Complex 1/2 (Tsc1/2)supporting

confidence: 87%

“…The proteins encoded by TSC1 and TSC2, hamartin and tuberin, dimerise to form a regulatory protein upstream of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signalling pathway that regulates cell growth. Dysregulation of the mTOR pathway is an intrinsic characteristic of PanNETs and has been successfully targeted by the drug everolimus (Larson et al 2012, Koc et al 2017.…”

Section: Tuberous Sclerosis Complex 1/2 (Tsc1/2)mentioning

confidence: 99%

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The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

Pipinikas

Berner

Sposito

et al. 2019

Endocrine-Related Cancer

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Neuroendocrine neoplasms (NENs) are a relatively rare group of heterogeneous tumours originating from neuroendocrine cells found throughout the body. Pancreatic NENs (PanNENs) are the second most common pancreatic malignancy accounting for 1–3% of all neoplasms developing in the pancreas. Despite having a low background mutation rate, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes (PTEN, TSC1/2) are implicated in disease development and progression. Their increased incidence coupled with advances in sequencing technologies has reignited the interest in PanNEN research and has accelerated the acquisition of molecular data. Studies utilising such technological advances have further enriched our knowledge of PanNENs’ biology through novel findings, including higher-than-expected presence of germline mutations in 17% of sporadic tumours of no familial background, identification of novel mutational signatures and complex chromosomal rearrangements and a dysregulated epigenetic machinery. Integrated genomic studies have progressed the field by identifying the synergistic action between different molecular mechanisms, while holding the promise for deciphering disease heterogeneity. Although our understanding is far from being complete, these novel findings have provided the optimism of shaping the future of PanNEN research, ultimately leading to an era of precision medicine for NETs. Here, we recapitulate the existing knowledge on pancreatic neuroendocrine tumours (PanNETs) and discuss how recent, novel findings have furthered our understanding of these complex tumours.

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Section: Tuberous Sclerosis Complex 1/2 (Tsc1/2)supporting

confidence: 87%

Section: Tuberous Sclerosis Complex 1/2 (Tsc1/2)mentioning

confidence: 99%

The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

Pipinikas

Berner

Sposito

et al. 2019

Endocrine-Related Cancer

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“…The frequencies of PanNET are higher in MEN1 (30%-80%) and VHL (17%) 27,28 ; they are extremely rare in NF1 and TSC. 29 However, NF1-associated duodenal and ampullary somatostatinoma is more common. 30 Recently, a fifth hereditary PanNET has been described in a few isolated cases and is currently given the name of Mahvash disease, which is an autosomal recessive hereditary condition with homozygous or biallelic heterozygous mutation of glucagon receptor.…”

Section: Pathologic Features and Morphologicmentioning

confidence: 99%

Pancreatic Neuroendocrine Neoplasms: Landscape and Horizon

Tang

2020

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Since the initial description of pancreatic endocrine physiology and the recognition of islet cell tumors in the 1800s, there have been noteworthy advances in the pathobiology of pancreatic neuroendocrine neoplasms (PanNENs), and definition of the important distinction between well-differentiated neuroendocrine tumor (PanNET) and poorly differentiated neuroendocrine carcinoma (PanNEC). The evolving knowledge has resulted in a continuous update in terminology, classification, and grading system for this group of neoplasms. Pancreatic neuroendocrine tumors associated with hereditary conditions have been linked to unique molecular and genetic events, and sporadic PanNETs have specific gene signatures. Based on accumulative experience and knowledge, therapeutic strategies have been defined for this group of neoplasms. Objective.— To review the evolution and description of the pathologic-genomic evolution of PanNENs, and to facilitate accurate pathologic interpretation for the corresponding clinical management. Data Sources.— Literature review of published studies and author's own work. Conclusions.— Evolving experience and knowledge have established subtypes of pancreatic neuroendocrine neoplasms, based on their genotype and phenotype. Accurate pathologic interpretation of the specific neoplasm has significant implications for therapy and prognosis.

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“…It is caused by pathogenic variants in either of the TSC1 or TSC2 genes resulting in the loss of functioning protein products hamartin or tuberin, respectively, and subsequent constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) [2,3]. The increased mTOR activation results in benign tumor growth in various organs of the body, mainly the brain, kidneys, skin, lungs, eyes, and liver [2,3], although there have been reports of other less common organ involvement such as bone and pancreas [4,5]. Neurologic involvement is the most common cause of morbidity in this condition, with epilepsy developing in up to 90% of patients with TSC, often within the first year of life [6,7].…”

Section: Introductionmentioning

confidence: 99%

Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures

Lechuga

Franz

2019

Expert Review of Neurotherapeutics

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Introduction: Tuberous sclerosis complex (TSC) is a rare genetic disorder resulting in benign tumors in various organs. It is caused by mutations in TSC1 or TSC2 genes causing hyperactivation of the mammalian target of rapamycin (mTOR) pathway. The majority of patients with TSC develop epilepsy, and approximately two-thirds become refractory to antiepileptic drugs (AEDs). Recently, the mTOR inhibitor everolimus was approved as adjunctive therapy for TSC-associated partial seizures. Areas covered: This article covers different characteristics of everolimus, including major clinical trials leading to its approval in TSC-associated partial seizures, safety concerns, drug pharmacokinetics/ pharmacodynamics, and an overview of potential competitors and other agents used to treat TSCassociated seizures. Expert opinion: Unlike many other therapies for treating TSC-associated seizures, everolimus addresses the underlying pathophysiology of TSC, and since it has also been shown to improve other TSC manifestations such as subependymal giant cell astrocytomas and renal angiomyolipomas, everolimus provides a potential multisystemic therapy for TSC. An important avenue for future research is exploring the possible use of everolimus as a preventative treatment for seizures as there is the potential to prevent negative developmental outcomes associated with TSC.

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Pancreatic tumors in children and young adults with tuberous sclerosis complex

Abstract: Pancreatic tumor is relatively common in children and young adults with tuberous sclerosis complex.

Cited by 35 publications

References 26 publications

The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

Pancreatic Neuroendocrine Neoplasms: Landscape and Horizon

Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures

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