A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors

Malczewska, Anna; Kidd, Mark; Matar, Somer; Kos–Kudła, Beata; Modlin, Irvin M.

doi:10.1159/000487326

Cited by 65 publications

(73 citation statements)

References 101 publications

(153 reference statements)

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“…miRNA biomarkers [63] either derived from tumour cells or from the local microenvironment have passed the early developmental stages and are now undergoing investigation [90]. Recent longitudinal assessment of miRNA profiling in SBNEN undergoing resection demonstrated an ability to discriminate between SBNEN patients and healthy controls with an area under the curve (AUC) of 0.951, with capabilities in identifying residual and recurrent disease [91].…”

Section: T -Primary Tumourmentioning

confidence: 99%

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

et al. 2019

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The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeu-tic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.According to SEER version 18, SBNEN and PanNEN incidences are currently estimated at 1.2 and 0.7 per 100,000, respectively [5]. The overall 20-year duration prevalence of all NEN is estimated at 171,321; SBNEN constituting 32,122 patients with 3-fold fewer PanNEN (10,707) [5]. Possible attributable factors for this increase evolving epidemiology include increased use of endoscopy and also improvements in the sensitivity of widely used imaging modalities, leading to increased detection of early-stage, asymptomatic disease [5].The median overall survival (OS) for NEN (irrespective of site and grade) is 9.3 years [5]. For SB (median OS: 14 years), this ranges from 70 months (advanced disease with distant metastases) to 170 months (localised disease) and from 30 months (Grade 3) to 160 months (Grade 1). For pancreas (median OS: 3.6 years): 21 months (advanced) to 235 months (localised disease) and from 15 months (Grade 3) to 140 months (Grade 1) [5].Multivariable analyses have identified that ethnicity, age, differentiation, stage and site all have statistically significant correlations with survival. In general, Caucasian ethnicity, age (< 50 years) and localised, well-differentiated NEN exhibit the best survival. SB tumour patients are approximately 1.5 times more likely to survive longer than those with PanNEN [19]. Many of these correlations are self-evident since they pertain to degree of malignancy, disease duration and patient performance status.OS (median 5-year) app...

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Section: T -Primary Tumourmentioning

confidence: 99%

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

et al. 2019

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“…We are not aware of any studies focused on circulating miRs in EAS or in patients with CD. Nevertheless, circulating miR-182, 196a, 200a, 21-5p, 22-3p, and 7-5p were upregulated and miR-31, 129-5p, 133a, 215, and 150-5p were downregulated in patients with small bowel neuroendocrine tumors (9,(36)(37)(38). Downregulation of miR has been observed in plasma samples of patients with pituitary adenoma compared to samples from healthy subjects (39).…”

Section: Discussionmentioning

confidence: 99%

“…However, the BIPSS procedure is invasive, costly and has certain contraindications and potential complications (7). Bloodcirculating microRNAs (miRs) are current promising biomarkers in cancer diagnosis and monitoring (8,9) as well as in some metabolic diseases (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Circulating Plasma microRNA to Differentiate Cushing's Disease From Ectopic ACTH Syndrome

Belaya¹,

Khandaeva²,

Nonn

et al. 2020

Front. Endocrinol.

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Corticotropinomas and adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors exhibit differential levels of some microRNAs (miRs) compared to normal tissue. Because miRs can be released from tissues into circulation, they offer promise as novel disease biomarkers. Objective: To evaluate whether miRs are differentially detected in plasma samples of patients with ACTH-dependent Cushing's syndrome (CS). Design: Case-control study. Methods: Morning fasting plasma samples were collected from 41 consecutive patients with confirmed ACTH-dependent CS and 11 healthy subjects and stored at −80 • C. Twenty-one miRs previously reported to be differentially expressed in ACTH-secreting tumors vs. healthy tissue samples were quantified in plasma by qPCR. Results: Among enrolled subjects, 28 were confirmed to have Cushing's disease (CD), 13 had ectopic ACTH secretion (EAS) and 11 were healthy controls. We found statistically significant differences in the circulating levels of miR-16-5p [45.04 (95% CI 28.77-61.31) in CD vs. 5.26 (2.65-7.87) in EAS, P < 0.001; q = 0.001], miR-145-5p [0.097 (0.027-0.167) in CD vs. undetectable levels in EAS, P = 0.008; q = 0.087] and differences in miR-7g-5p [1.842 (1.283-2.400) in CD vs. 0.847 (0.187-1.507) in EAS, P = 0.02; q = 0.14]. The area under the receiver-operator (ROC) curve was 0.879 (95% CI 0.770-0.987), p < 0.001, when using miR-16-5p to distinguish between CD and EAS. Circulating levels of miR-16-5p in the healthy control group differed from that of both the CD and EAS groups. Conclusions: Plasma miR levels differ in patients with CD and EAS. In particular, miR-16-5p, miR-145-5p and miR-7g-5p are promising biomarkers for further research to differentiate ACTH-dependent CS.

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“…Altered expression of specific miRNAs has been reported between normal, benign, and malignant tissues of MEN1-associated NETs, including pituitary [ 19 , 20 , 21 ], parathyroid [ 22 , 23 ], and GEP tract [ 24 , 25 ] tumors. Results from a previous study of our Research Group showed that menin is a direct target of miR-24-1, and that this miRNA may contribute to MEN1 parathyroid tumorigenesis [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Multiple Endocrine Neoplasia Type 1: The Potential Role of microRNAs in the Management of the Syndrome

Donati

Ciuffi²,

Marini³

et al. 2020

IJMS

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Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited tumor syndrome, characterized by the development of multiple neuroendocrine tumors (NETs) in a single patient. Major manifestations include primary hyperparathyroidism, gastro-entero-pancreatic neuroendocrine tumors, and pituitary adenomas. In addition to these main NETs, various combinations of more than 20 endocrine and non-endocrine tumors have been described in MEN1 patients. Despite advances in diagnostic techniques and treatment options, which are generally similar to those of sporadic tumors, patients with MEN1 have a poor life expectancy, and the need for targeted therapies is strongly felt. MEN1 is caused by germline heterozygous inactivating mutations of the MEN1 gene, which encodes menin, a tumor suppressor protein. The lack of a direct genotype–phenotype correlation does not permit the determination of the exact clinical course of the syndrome. One of the possible causes of this lack of association could be ascribed to epigenetic factors, including microRNAs (miRNAs), single-stranded non-coding small RNAs that negatively regulate post-transcriptional gene expression. Some miRNAs, and their deregulation, have been associated with MEN1 tumorigenesis. Recently, an extracellular class of miRNAs has also been identified (c-miRNAs); variations in their levels showed association with various human diseases, including tumors. The aim of this review is to provide a general overview on the involvement of miRNAs in MEN1 tumor development, to be used as possible targets for novel molecular therapies. The potential role of c-miRNAs as future non-invasive diagnostic and prognostic biomarkers of MEN1 will be discussed as well.

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A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors

Cited by 65 publications

References 101 publications

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

Circulating Plasma microRNA to Differentiate Cushing's Disease From Ectopic ACTH Syndrome

Multiple Endocrine Neoplasia Type 1: The Potential Role of microRNAs in the Management of the Syndrome

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