Translational Diagnostics and Therapeutics in Pancreatic Neuroendocrine Tumors

Maxwell, Jessica; Sherman, Scott K.; Howe, James R.

doi:10.1158/1078-0432.ccr-16-0435

Cited by 19 publications

(23 citation statements)

References 77 publications

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“…Activation of the PI3K/Akt/mTOR pathway (one of the RAS downstream signaling pathways) promotes cell biosynthesis through multiple actions, including increasing the surface expression of nutrient transporters, increasing glycolysis and lactate production, and enhancing the biosynthesis of macromolecules, as discussed in (8, 32, 42). These effects are, in part, mediated through oxygen independent HIF-α stabilization and activation of HIF signaling.…”

Section: Mitochondria Krebs Cycle and Cancer Cell Metabolismmentioning

confidence: 99%

Pheochromocytoma: The First Metabolic Endocrine Cancer

Jochmanová

Pacák

2016

Clinical Cancer Research

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Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics allowed us to take a closer look at the metabolic changes present in pheochromocytomas and paragangliomas (PHEOs/PGLs). These neuroendocrine tumors often exhibit dysregulation of mitochondrial metabolism, which is driven by mutations in genes encoding Krebs cycle enzymes or by activation of hypoxia signaling. Present metabolic changes are involved in processes associated with tumorigenesis, invasiveness, metastasis, and resistance to various cancer therapies. In this review, we discuss the metabolic nature of PHEOs/PGLs and how unveiling the metabolic disturbances present in tumors could lead to identification of new biomarkers and personalized cancer therapies.

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Section: Mitochondria Krebs Cycle and Cancer Cell Metabolismmentioning

confidence: 99%

Pheochromocytoma: The First Metabolic Endocrine Cancer

Jochmanová

Pacák

2016

Clinical Cancer Research

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“…One study showed that the median survival for patients with WD-NET versus patients with PD-NEC was 75 months and 11 months respectively, indicative of the diagnostic importance of properly classifying these tumors. 14 Multiple studies have attempted to classify these tumors based on the mitotic rate as well as the Ki-67 proliferative index (Ki-67 proliferative index is used by the European Endocrine Tumor Society as a means to assess the grade of the tumor; part of 2010 WHO grading). 1 Very little consensus was obtained in previous studies in a large proportion of cases (66%) based on histological features alone.…”

Section: Discussionmentioning

confidence: 99%

“…Maxwell et al proposed a model for the likely genomic mechanisms of tumorigenesis in inherited as well as sporadic PanNETs. 14 The main mechanisms proposed by Maxwell et al for genomic alteration in PanNETs include 1) Somatic homozygous mutation with loss of heterozygosity or 2) Somatic heterozygous mutation with epigenetic silencing. 14…”

Section: Discussionmentioning

confidence: 99%

Site-Specific Genomic Alterations in a Well-Differentiated Pancreatic Neuroendocrine Tumor With High-Grade Progression

Martín¹,

LaBauve²,

Pomo³

et al. 2018

Pancreas

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The major categories of pancreatic neuroendocrine tumor (PanNET) are well-differentiated NET and poorly differentiated neuroendocrine carcinoma. Sequencing of these tumors has identified multiple important genes in the pathogenesis of PanNETs, such as DAXX/ATRX, MEN1, TP53, RB, and mTOR pathway genes. We identified a case of well-differentiated PanNET with high-grade progression with simultaneous low- and high-grade histologic regions containing variable genomic profiles. We performed tumor microdissection and analyzed both regions using a 409-gene comprehensive cancer panel using next-generation sequencing in addition to immunohistochemical and morphologic studies. The low-grade region showed a change in the DAXX gene as a copy number variant (CNV) deletion. The high-grade region showed CNV deletion changes in the DAXX gene as well as the MEN1 gene. We observed additional mutational changes in the PTEN gene and SMAD4 gene in the high-grade region. Our data support that high-grade progression in PanNETs may be the result of the progressive accumulation of genetic changes (CNVs and point mutational changes) within the body of the tumor. Next generation sequencing may provide pathologists and clinicians with ancillary information to accurately characterize and treat these tumors.

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“…Syndromic pituitary adenomas MEN1 syndrome. MEN1 is characterized by the presence of the classical triad of hyperparathyroidism (in almost all patients by the age of 50 years), pituitary adenomas (in about 30%-40% of cases), and neuroendocrine tumors [in about 60% of cases; further data on neuroendocrine tumors can be found in the CCR Focus article by Maxwell and colleagues (50)]. In addition, other tumor types have also been associated with this syndrome, such as facial angiofibromas (85%), collagenomas (72%), adrenal cortical adenomas (40%), lipomata (30%), meningiomas (8%), pheochromocytomas (rarely).…”

Section: Isolated Pituitary Adenomasmentioning

confidence: 99%

Novel Genetic Causes of Pituitary Adenomas

Caimari

Korbonits

2016

Clinical Cancer Research

109

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Recently, a number of novel genetic alterations have been identified that predispose individuals to pituitary adenomas. Clinically relevant pituitary adenomas are relatively common, present in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior lobe of the pituitary gland, and cause disease due to hormonal alterations and local space-occupying effects. The pathomechanism of pituitary adenomas includes alterations in cell-cycle regulation and growth factor signaling, which are mostly due to epigenetic changes; somatic and especially germline mutations occur more rarely. A significant proportion of growth hormone- and adrenocorticotrophin-secreting adenomas have activating somatic mutations in the GNAS and USP8 genes, respectively. Rarely, germline mutations predispose to pituitary tumorigenesis, often in a familial setting. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and McCune-Albright syndrome. Pituitary tumors have also been described in association with neurofibromatosis type 1, DICER1 syndrome, and SDHx mutations. Pituitary adenomas with no other associated tumors have been described as familial isolated pituitary adenomas. Patients with AIP or GPR101 mutations often present with pituitary gigantism either in a familial or simplex setting. GNAS and GPR101 mutations that arise in early embryonic age can lead to somatic mosaicism involving the pituitary gland and resulting in growth hormone excess. Senescence has been suggested as the key mechanism protecting pituitary adenomas turning malignant in the overwhelming majority of cases. Here we briefly summarize the genetic background of pituitary adenomas, with an emphasis on the recent developments in this field. Clin Cancer Res; 22(20); 5030-42. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".

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Translational Diagnostics and Therapeutics in Pancreatic Neuroendocrine Tumors

Cited by 19 publications

References 77 publications

Pheochromocytoma: The First Metabolic Endocrine Cancer

Pheochromocytoma: The First Metabolic Endocrine Cancer

Site-Specific Genomic Alterations in a Well-Differentiated Pancreatic Neuroendocrine Tumor With High-Grade Progression

Novel Genetic Causes of Pituitary Adenomas

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