Genomic characterization of a well-differentiated grade 3 pancreatic neuroendocrine tumor

Williamson, Laura; Steel, Michael J.; Grewal, Jasleen K.; Thibodeau, My Lihn; Zhao, Eric Y.; Loree, Jonathan M.; Yang, Kevin; Gorski, Sharon M.; Mungall, Andrew J.; Moore, Richard A.; Marra, Marco A.; Laskin, Janessa; Renouf, Daniel J.; Schaeffer, David F.; Jones, Steven J.M.

doi:10.1101/mcs.a003814

Cited by 23 publications

(16 citation statements)

References 52 publications

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“…On the other hand, there are possible causes for the formation of PanNETs in mice by Rb abnormalities. For example, there have been reports of copy-number alteration (35), mutation (8), and upstream abnormalities of Rb pathway including CDK4/6 (10, 11), p27 (36,37), RABL6A (38,39) in human PanNETs. Thus, abnormalities of Rb pathway other than Rb gene alteration may be involved in PanNETs.…”

Section: Discussionmentioning

confidence: 99%

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors

et al. 2020

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Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rb f/f ) in mice did not affect pancreatic exocrine cells, the a-cell/b-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated Pan-NET with a Ki67-labeling index of 2.7%. In contrast, pancreasspecific induction of a p53 mutation (Pdx1-Cre;Trp53 R172H ) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre; Trp53 R172H ;Rb f/f ) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53 R172H ;Rb f/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET.Significance: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).

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Section: Discussionmentioning

confidence: 99%

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors

et al. 2020

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“…Mutations in other components of the PI3K/mTOR signaling pathway including PTEN, DEPDC5, and PIK3CA have also been observed in well differentiated pancreatic NET [16,17,19]. In a case report on one patient with metastatic pancreatic NET G−3, the whole-genome sequencing of liver metastases exhibited a TSC1-disrupting fusion, showed a novel CHD7-BEND2 fusion, but lacked any somatic variants in ATRX, DAXX, and MEN1 [20]. To our knowledge, the majority of molecular biology results is focused on pancreatic NET G−3.…”

Section: Molecular Biologymentioning

confidence: 99%

Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review

Pellat

Coriat

2020

JCM

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The 2017 World Health Organization (WHO) classification of neuroendocrine neoplasms (NEN) of the digestive tract introduced a new category of tumors named well-differentiated grade 3 neuroendocrine tumors (NET G−3). These lesions show a number of mitosis, or a Ki−67 index higher than 20% with a well-differentiated morphology, therefore separating them from neuroendocrine carcinomas (NEC) which are poorly differentiated. It has become clear that NET G−3 show differences not only in morphology but also in genotype, clinical presentation, and treatment response. The incidence of digestive NET G−3 represents about one third of NEN G−3 with main tumor sites being the pancreas, the stomach and the colon. Treatment for NET G−3 is not yet standardized because of lack of data. In a non-metastatic setting, international guidelines recommend surgical resection, regardless of tumor grading. For metastatic lesion, chemotherapy is the main treatment with similar regimen as NET G−2. Sunitinib has also shown some positive results in a small sample of patients but this needs confirmation. Peptide receptor radionuclide therapy (PRRT) and immunotherapy could be future available treatments after ongoing studies. The goal of this review was to sum up the latest data on the epidemiology and management of digestive NET G−3.

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“…Larger tumor size, higher grade, and liver metastases indicate a less favorable prognosis [ 1 , 2 ]. While the majority of PNETs are moderately malignant and slow-growing, PDACs, which account for more than 90% of pancreatic malignancies, are particularly aggressive, with rapidly infiltrative growth [ 3 , 4 ]. Nonfunctional PNETs and PDACs are characterized by a relatively long asymptomatic course, and, therefore, diagnosis of both types of pancreatic neoplasia is often made in advanced tumor stages.…”

Section: Introductionmentioning

confidence: 99%

“…The histological diagnosis of neuroendocrine tumors is confirmed by immunohistochemical analysis of chromogranin A and synaptophysin expression and the Ki-67/MIB1 proliferation index [ 1 , 3 ]. However, the histological differentiation grade (G) is the most important clinical characteristic [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Differences between Well-Differentiated Neuroendocrine Tumors and Ductal Adenocarcinomas of the Pancreas Assessed by Multi-Omics Profiling

Starzyńska

Karczmarski

Paziewska

et al. 2020

IJMS

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Most pancreatic neuroendocrine tumors (PNETs) are indolent, while pancreatic ductal adenocarcinomas (PDACs) are particularly aggressive. To elucidate the basis for this difference and to establish the biomarkers, by using the deep sequencing, we analyzed somatic variants across coding regions of 409 cancer genes and measured mRNA/miRNA expression in nine PNETs, eight PDACs, and four intestinal neuroendocrine tumors (INETs). There were 153 unique somatic variants considered pathogenic or likely pathogenic, found in 50, 57, and 24 genes in PDACs, PNETs, and INETs, respectively. Ten and 11 genes contained a pathogenic mutation in at least one sample of all tumor types and in PDACs and PNETs, respectively, while 28, 34, and 11 genes were found to be mutated exclusively in PDACs, PNETs, and INETs, respectively. The mRNA and miRNA transcriptomes of PDACs and NETs were distinct: from 54 to 1659 differentially expressed mRNAs and from 117 to 250 differentially expressed miRNAs exhibited high discrimination ability and resulted in models with an area under the receiver operating characteristics curve (AUC-ROC) >0.9 for both miRNA and mRNA. Given the miRNAs high stability, we proposed exploring that class of RNA as new pancreatic tumor biomarkers.

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Genomic characterization of a well-differentiated grade 3 pancreatic neuroendocrine tumor

Cited by 23 publications

References 52 publications

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors

Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review

Differences between Well-Differentiated Neuroendocrine Tumors and Ductal Adenocarcinomas of the Pancreas Assessed by Multi-Omics Profiling

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