Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis

Hackeng, Wenzel M.; Brosens, Lodewijk A.A.; Poruk, Katherine E.; Noë, Michaël; Hosoda, Waki; Poling, Justin; Rizzo, Anthony; Campbell-Thompson, Martha; Atkinson, Mark A.; Konukiewitz, Björn; Klöppel, Günter; Heaphy, Christopher M.; Meeker, Alan K.; Wood, Laura D.

doi:10.1016/j.humpath.2016.06.006

Cited by 34 publications

(33 citation statements)

References 20 publications

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“…Mutations of MEN1 have been found in 30% of sporadic NF-PanNET, 7% of insulinomas, 36% of gastrinomas, 67% of glucagonomas and 44% of VIPomas (Moore et al 2001). A recent study on microadenomas (considered precursors to PanNET in MEN1 patients) identified aberrant menin expression in 74% of the cases (14/19), suggesting that in this subset of cases, aberrant menin expression is a key initiator in PanNET tumorigenesis (Kloppel et al 2014, Esposito et al 2015, Hackeng et al 2016. Men1 encodes the transcription factor menin, which recruits the H3K4me3 histone methyltransferase mixed lineage leukaemia (MLL1) complex that plays an essential role in chromatin remodelling and gene expression (Agarwal et al 1999).…”

Section: Chromatinmentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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Section: Chromatinmentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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“…Only a few previous studies have conducted biomarker evaluations for neuroendocrine microadenomas [12,25,26]. Decreased menin expression and increased cytokeratin 19 expression have been reported in neuroendocrine microadenomas [25,26]. However, controversy exists over the loss of ATRX or DAXX expression in these tumors [12,26,27].…”

Section: Discussionmentioning

confidence: 99%

Loss of Progesterone Receptor Expression Is an Early Tumorigenesis Event Associated with Tumor Progression and Shorter Survival in Pancreatic Neuroendocrine Tumor Patients

Kim

Lee

et al. 2017

J Pathol Transl Med

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BackgroundPancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic neoplasms and there is no well-elucidated biomarker to stratify their detection and prognosis. Previous studies have reported that progesterone receptor (PR) expression status was associated with poorer survival in PanNET patients.MethodsTo validate previous studies, PR protein expression was assessed in 21 neuroendocrine microadenomas and 277 PanNETs and compared with clinicopathologic factors including patient survival.ResultsPR expression was gradually decreased from normal islets (49/49 cases, 100%) to neuroendocrine microadenoma (14/21, 66.6%) to PanNETs (60/277, 21.3%; p < .001). PanNETs with loss of PR expression were associated with increased tumor size (p < .001), World Health Organization grade (p = .001), pT classification (p < .001), perineural invasion (p = .028), lymph node metastasis (p = .004), activation of alternative lengthening of telomeres (p = .005), other peptide hormonal expression (p < .001) and ATRX/DAXX expression (p = .015). PanNET patients with loss of PR expression (5-year survival rate, 64.1%) had significantly poorer recurrence-free survival outcomes than those with intact PR expression (90%) by univariate (p = .012) but not multivariate analyses. Similarly, PanNET patients with PR expression loss (5-year survival rate, 76%) had significantly poorer overall survival by univariate (p = .015) but not multivariate analyses.ConclusionsLoss of PR expression was noted in neuroendocrine microadenomas and was observed in the majority of PanNETs. This was associated with increased grade, tumor size, and advanced pT and pN classification; and was correlated with decreased patient survival time by univariate but not multivariate analyses. Loss of PR expression can provide additional information on shorter disease-free survival in PanNET patients.

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“…7 Moreover, Hadano et al found that pancreatic NEMAs and NETs have distinct molecular profiles. 7 Moreover, Hadano et al found that pancreatic NEMAs and NETs have distinct molecular profiles.…”

Section: Demonstrated That Loss Ofmentioning

confidence: 99%

“…Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and alternative lengthening of telomere phenotype are relatively late events. 7 Moreover, Hadano et al found that pancreatic NEMAs and NETs have distinct molecular profiles. 8 Although morphologic criteria for NET in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens are well-defined and the diagnosis is often straightforward, reports regarding NEMA cytology are extremely rare.…”

Section: Demonstrated That Loss Ofmentioning

confidence: 99%

Pancreatic neuroendocrine microadenomatosis: A case report of cytology and histology correlation

Cohen

Dillhoff

et al. 2016

Diagnostic Cytopathology

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Pancreatic neuroendocrine neoplasia is categorized by grade, size, and functional status. Neuroendocrine microadenoma (NEMA) is defined as a neuroendocrine tumor (NET) that measures less than 0.5 cm in diameter. Multiple NEMAs are termed neuroendocrine adenomatosis (NEMAtosis). The surgical pathology and clinical aspects of pancreatic NEMAtosis have been reported, but there has been no report regarding EUS-FNA cytology of NEMAtosis. We report a case of NEMAtosis with cytologic correlation and illustrate the diagnostic challenges and potential pitfalls. The pre-operative cytology can be problematic. The main differential diagnosis of the EUS-FNA specimen includes NET, normal pancreas, and islet cell hyperplasia/aggregation associated with chronic pancreatitis. The helpful cytopathologic feature of NEMAtosis is the presence of two intermingled populations of loosely-cohesive neuroendocrine cell clusters and tight acinar cell groups arranged in microacinar and/or grape-like structures. Although neuroendocrine cells and acinar cells possess different cytomorphology, the distinction is not always straightforward because both types of cells are small and cytologically bland. Cytologic assessment of both architecture and individual cell morphology is imperative to avoid interpretation error and further guide appropriate clinical management. Diagn. Cytopathol. 2017;45:143-147. © 2016 Wiley Periodicals, Inc.

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Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis

Cited by 34 publications

References 20 publications

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Loss of Progesterone Receptor Expression Is an Early Tumorigenesis Event Associated with Tumor Progression and Shorter Survival in Pancreatic Neuroendocrine Tumor Patients

Pancreatic neuroendocrine microadenomatosis: A case report of cytology and histology correlation

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