Molecular Profiling of Pancreatic Neuroendocrine Tumors in Sporadic and Von Hippel-Lindau Patients

Speisky, Daniela; Ducès, Aurélie; Bièche, Ivan; Rebours, Vinciane; Hammel, Pascal; Sauvanet, Alain; Richard, Stéphane; Bédossa, Pierre; Vidaud, Michel; Murat, A.; Niccoli, Patricia; Scoazec, Jean‐Yves; Ruszniewski, Philippe; Couvelard, Anne

doi:10.1158/1078-0432.ccr-11-2759

Cited by 60 publications

(33 citation statements)

References 48 publications

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“…Activating CDK4 mutations ( R24C and R24H ) that prevent inhibition by p16 INK4A increase melanoma risk [80]. Intriguingly, loss of p16 INK4A also contributes to pancreatic neuroendocrine tumours, which include islet tumours such as insulinomas [81–85]. Paradoxically, when not deleted, p16 INK4A may be overexpressed in tumours and transformed cells [86, 87].…”

Section: General Biology Of Cdkn2a/b Locus Genesmentioning

confidence: 99%

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Islet biology, the CDKN2A/B locus and type 2 diabetes risk

et al. 2016

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Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16INK4A to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16INK4A) and three other gene products, p14 alternate reading frame (p14ARF), p15INK4B and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

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Section: General Biology Of Cdkn2a/b Locus Genesmentioning

confidence: 99%

“…In a single study, CDKN2A/B polymorphisms were not associated with AIR max , a surrogate for beta cell mass [207]. On the other hand, the contribution of p16 INK4A loss to pancreatic neuro endocrine tumour risk may imply a role in human islet cell proliferation [81–85]. …”

Section: Evidence That Human Cdkn2a/b-related Type 2 Diabetes Risk Inmentioning

confidence: 99%

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

et al. 2016

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“…The VHL gene is a tumor suppressor gene leading to the expression of a protein responsible for HIF degradation. Its mutation or inactivation leads to the accumulation of the HIF protein and to a "pseudohypoxic" state with enhanced transcription of specific target genes such as CA9 and GLUT1 [32]. In digestive NEN, the VHL pathway may play an important role -for example, in patients with VHL disease.…”

Section: Discussionmentioning

confidence: 99%

18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation

Bucau¹,

Laurent-Bellue²,

Poté³

et al. 2017

Neuroendocrinology

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Background:¹⁸F-FDG-PET scan positivity correlates with poor prognosis in neuroendocrine neoplasms (NEN). Glucose transporter 1 (GLUT1) and carbonic anhydrase 9 (CA9) are markers of aggressiveness in tumors. Together with von Hippel-Lindau protein (pVHL), they are involved in tumor cell metabolism via the hypoxia-inducible factor signaling pathway. The aim of this study was to compare, in a series of well-differentiated neuroendocrine tumors (NET), the ¹⁸F-FDG uptake and expression of the proliferation markers Ki-67, GLUT1, CA9, and pVHL. Patients and Methods: This retrospective study included 27 patients with well-differentiated NET. ¹⁸F-FDG-PET images were evaluated by the maximum standardized uptake value (SUV_max). GLUT1, CA9, and pVHL were analyzed by immunohistochemistry. Results: The NET were of pancreatic (n = 19), midgut (n = 4), duodenal (n = 1), esophageal (n = 1), rectal (n = 1), and pulmonary (n = 1) origin. Eight, 11, and 8 tumors were grade 1, 2, and 3, respectively. The mean/median Ki-67 index was 15/10% (1-60). The mean/median SUV_max was 6.2/5.2 (1.4-18.7). SUV_max correlated with greater tumor size (p = 0.03), higher expression of Ki-67 (p = 0.04), and lower expression of pVHL (p = 0.008). In the group of 16 NET with a low proliferative index (Ki-67 index <10%), 5/6 (83%) of the tumors with a high SUV_max had decreased pVHL expression (p = 0.0013). Conclusion: This study confirms that ¹⁸F-FDG-PET uptake correlates with both tumor size and proliferation in well-differentiated NET, and it highlights a subset of low-grade but ¹⁸F-FDG-PET-positive NET related to sporadic inactivation of the VHL pathway.

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“…VHL is a tumor suppressor gene in VHL disease in which PanNETs are observed in 12% to 17% of cases [36]. Mutation of VHL causes disruption of the interaction between the transcription factor HIF and VHL protein, leading to constitutive HIF activation and expression of HIF targets, affecting many cellular processes such as angiogenesis and cell metabolism [37,38]. One case of a VHL mutation in our study could be considered sporadic because the mutation was observed only in the tumor and not in a non-tumor sample.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Cancer-related Genes Associated with Grading of Well Differentiated Pancreatic Neuroendocrine Neoplasms

Yokota¹,

Fukasawa²,

Takano³

et al. 2017

Pancreat Disord Ther

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Objectives: Although recent advances in next-generation sequencing (NGS) have revealed some genetic alterations in various tumors, including pancreatic neuroendocrine tumors (PanNETs), their clinical significance is not fully understood. To investigate the clinical significance of gene alteration in PanNETs, we performed genetic analysis of well differentiated PanNETs using NGS.Methods: Twenty-nine resected primary PanNET tissue samples and three samples of metastatic liver tissues, obtained from 29 PanNET patients, were analyzed. DNA was extracted from laser-captured formalin-fixed paraffinembedded tissues, and 50 cancer-associated genes, including approximately 2,800 hotspots, were amplified by multiplex PCR. Amplified libraries were sequenced using NGS, and the results were analyzed in conjunction with respective clinicopathological features. Results:Among 50 investigated genes, somatic mutations were observed in four of 29 PanNET cases. We identified APC mutations in three cases, PTEN in two, and VHL and STK11 in one. The identified mutations were observed only in NET G2 tumors. All liver metastases contained at least one mutation, such as PTEN or TP53, which was not observed in the primary tumor. Conclusion:The cancer-related gene mutations observed in PanNETs were associated with G2 grade tumors. The mutations were more frequent in PanNET liver metastasis than in the primary tumors. Our analysis of liver metastasis cases suggested that cancer-related gene mutations might raise the tumor grade and promote liver metastasis. Further studies of associations between genetic alterations and clinicopathological features should help in the cancer diagnosis and prediction of therapeutic effects of molecular-target drugs.

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Molecular Profiling of Pancreatic Neuroendocrine Tumors in Sporadic and Von Hippel-Lindau Patients

Cited by 60 publications

References 48 publications

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation

Alterations in Cancer-related Genes Associated with Grading of Well Differentiated Pancreatic Neuroendocrine Neoplasms

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