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Gene promoter hypermethylation in (A) sporadic NFPanNETs (SFRP5) and (B,C) MEN1 NFPanNETs (CDCA7L and RBM47, respectively) in comparison with normal islet cells. The methylation status of the genes was inversely associated with differential gene expression. CDCA7L indicates cell division cycle–associated 7‐like; MEN1, multiple endocrine neoplasia type 1; NFPanNET, nonfunctioning pancreatic neuroendocrine tumor; RBM47, RNA binding motif 47; SFRP5, secreted frizzle‐related protein 5.
Source publication
Background
Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome‐wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs.
Methods
Thirty‐three tissue samples were analyzed: they included samples from sporadic (n = 9), v...
Citations
... Despite improvements in prognostic grading and staging systems, the prediction of clinical behavior and response to specific therapies remains a challenge. DNA methylation is essential for tumorigenesis and could contribute to the identification of PanNET subgroups, and these subgroups could potentially be associated with clinical features [136][137][138]. A deeper understanding of the molecular mechanisms leading to the development of PanNETs is needed. ...
The alpha-thalassemia mental retardation X-linked (ATRX) syndrome protein is a chromatin remodeling protein that primarily promotes the deposit of H3.3 histone variants in the telomere area. ATRX mutations not only cause ATRX syndrome but also influence development and promote cancer. The primary molecular characteristics of ATRX, including its molecular structures and normal and malignant biological roles, are reviewed in this article. We discuss the role of ATRX in its interactions with the histone variant H3.3, chromatin remodeling, DNA damage response, replication stress, and cancers, particularly gliomas, neuroblastomas, and pancreatic neuroendocrine tumors. ATRX is implicated in several important cellular processes and serves a crucial function in regulating gene expression and genomic integrity throughout embryogenesis. However, the nature of its involvement in the growth and development of cancer remains unknown. As mechanistic and molecular investigations on ATRX disclose its essential functions in cancer, customized therapies targeting ATRX will become accessible.
... Those findings suggest that loss of RBM47 may arise as a consequence of inflammation during cancer progression in addition to cell-intrinsic pathways of downregulation associated with tumor initiation. Downregulation of RBM47 is observed with altered promoter methylation in neuroendocrine pancreatic tumors (46), suggesting yet another mechanism underlying a loss-of-function role in tumorigenesis. With the increasing burden of obesity and its pleiotropic effects on inflammation and cancer (47), it may become increasingly challenging to parse out distinct pathways in a physiological, in-vivo setting. ...
Rationale:
RNA binding protein 47 (RBM47) is required for embryonic endoderm development but a role in adult intestine is unknown.
Objective:
We studied intestine-specific Rbm47 knockout mice (Rbm47-IKO) following intestinal injury and made crosses into Apcmin/+ mice to examine alterations in intestinal proliferation, response to injury and tumorigenesis. We also interrogated human colorectal polyps and colon carcinoma tissue.
Findings:
Rbm47-IKO mice exhibit increased proliferation, abnormal villus morphology and cellularity, with corresponding changes in Rbm47-IKO organoids. Rbm47-IKO mice adapt to radiation injury and are protected against chemical-induced colitis, with Rbm47-IKO intestine showing upregulation of antioxidant and Wnt signaling pathways as well as stem cell and developmental genes. Furthermore, Rbm47-IKO mice are protected against colitis-associated cancer. By contrast, aged Rbm47-IKO mice develop spontaneous polyposis and Rbm47-IKO, Apcmin/+ mice manifest an increased intestinal polyp burden. RBM47 mRNA was decreased in human colorectal cancer versus paired normal tissue along with alternative splicing of TJP1 mRNA. Public databases revealed stage-specific reduction in RBM47 expression in colorectal cancer, associated independently with decreased overall survival.
Conclusions:
These findings implicate RBM47 as a cell-intrinsic modifier of intestinal growth, inflammatory and tumorigenic pathways.
... In addition to mutation events, epigenetic alterations have also been reported to contribute to neuroendocrine transformation, underlining the role of DNA methylation in driving tumorigenesis and stratifying prognosis in pNENs. Three pNEN subgroups were identified with distinct DNA methylation patterns (Lakis et al., 2021), particularly between NF-pNET subgroups (Tirosh et al., 2019). Aberrations in DNA methylation have been found in RASSF1A, GSTP1, CASP8, HIC1, TIMP3, VHL, MGMT, and other genes, including LINE-1 repetitive sequences (Stefanoli et al., 2014). ...
Pancreatic neuroendocrine neoplasms (pNENs) are rare cancers with broad challenges for their management. The main clinical obstacles are the high rate of patients diagnosed at advanced stages, lack of prognostic markers for early detection of disease recurrence in resected patients, significant limitations in identifying those who will benefit from adjuvant therapy, and timely recognition of treatment response. Therefore, the discovery of new prognostic and predictive markers is necessary for patient stratification and clinical management. Liquid biopsy, which has revolutionized the field of clinical oncology, is extremely under-investigated in pNENs. This review highlights its potential and the recent advances in related technologies, as candidates for the delivery of the new tools that can help to refine pNEN diagnosis and to personalize treatment. In addition, the opportunities and limitations of available preclinical research models with regard to biomarker research are discussed in light of pNEN clinical needs.
... Furthermore, MEN1-related PanNETs likewise have a high rate of promoter and genome-wide hypermethylation that is considered a distinctive feature of MEN1-related neoplasms [12,65]. In addition, MEN1 deficiency was reported to be associated with CpG hypermethylation contrary to sporadic or VHL-associated PanNETs [70]. These findings support the role of DNA methylation in PanNETs as being influenced by MEN1 mutations and may explain why MEN1 syndrome has inconsistent genotype-phenotype relationships [71]. ...
Current knowledge on the molecular landscape of pancreatic neuroendocrine tumors (PanNETs) has advanced significantly. Still, the cellular origin of PanNETs is uncertain and the associated mechanisms remain largely unknown. DAXX/ATRX and MEN1 are the three most frequently altered genes that drive PanNETs. They are recognized as a link between genetics and epigenetics. Moreover, the acknowledged impact on DNA methylation by somatic mutations in MEN1 is a valid hallmark of epigenetic mechanism. DAXX/ATRX and MEN1 can be studied at the immunohistochemical level as a reliable surrogate for sequencing. DAXX/ATRX mutations promote alternative lengthening of telomeres (ALT) activation, determined by specific fluorescence in situ hybridization (FISH) analysis. ALT phenotype is considered a significant predictor of worse prognosis and a marker of pancreatic origin. Additionally, ARX/PDX1 expression is linked to important epigenomic alterations and can be used as lineage associated immunohistochemical marker. Herein, ARX/PDX1 association with DAXX/ATRX/MEN1 and ALT can be studied through pathological assessment, as these biomarkers may provide important clues to the mechanism underlying disease pathogenesis. In this review, we present an overview of a new approach to tumor stratification based on genetic and epigenetic characteristics as well as cellular origin, with prognostic consequences.
... In pNETs, the presence of mutations in MEN1 also contributes to methylation status (77,78). In a study of 29 pNETs, CpG hypermethylation correlated with MEN1 loss when compared to sporadic or VHL-associated pNETs (77). ...
... In pNETs, the presence of mutations in MEN1 also contributes to methylation status (77,78). In a study of 29 pNETs, CpG hypermethylation correlated with MEN1 loss when compared to sporadic or VHL-associated pNETs (77). In a followup study, Tirosh, et al. examined 96 GEP-NEN samples by genome-wide methylation assays (querying a total of 835,424 CpGs). ...
Gastroenteropancreatic neuroendocrine neoplasms are a rare, diverse group of neuroendocrine tumors that form in the pancreatic and gastrointestinal tract, and often present with side effects due to hormone hypersecretion. The pathogenesis of these tumors is known to be linked to several genetic disorders, but sporadic tumors occur due to dysregulation of additional genes that regulate proliferation and metastasis, but also the epigenome. Epigenetic regulation in these tumors includes DNA methylation, chromatin remodeling and regulation by noncoding RNAs. Several large studies demonstrate the identification of epigenetic signatures that may serve as biomarkers, and others identify innovative, epigenetics-based targets that utilize both pharmacological and theranostic approaches towards the development of new treatment approaches.
... We then classified the papers according to the type of studied NET. Twenty-six studies were about Pan-NETs (59.1%) [10,11,[15][16][17][18][19][20]24,25,27,28,30,31,34,38,[41][42][43][45][46][47]49,[51][52][53], 3 studies had to do with (metastatic) liver NETs (6.8%) [36,37,44], 2 studies analyzed SI-NETs (4.5%) [14,35], whereas colon and rectum [12], rectum [22], non-specified GEP [39], and nonspecified GI NETs [50] had from 1 study each (2.3%). There were 4 studies with multiple types of NETs with separate data for each one of them provided (9.1%) [21,23,29,33], and another 2 studies with non-specified multiple types of NETs (4.5%) [13,48]. ...
... Regarding the source of data, there were 15 studies with histology-based analyses [10,15,20,23,24,33,[38][39][40][41][42][43]45,47,50] and another 15 studies with imaging-based analyses (34.1% each). Six studies were structured based on patient databases (16.7%) [13,22,27,29,32,48], 5 on genetic assays (11.4%) [18,21,30,35,36], and 3 on plasma/serum (6.8%) [12,14,26]. Imaging-based studies were further distinguished in CT-based (6/15, 40%) [17,28,34,46,51,53], EUS-based (4/15, 26.7%) [11,19,25,31], MRI-based (3/15, 20%) [44,49,52], and PET/CT (2/15, 13.3%) [16,37]. ...
... Imaging-based studies were further distinguished in CT-based (6/15, 40%) [17,28,34,46,51,53], EUS-based (4/15, 26.7%) [11,19,25,31], MRI-based (3/15, 20%) [44,49,52], and PET/CT (2/15, 13.3%) [16,37]. Genetic assays included gene expression assays [35,36] and miRNA analyses [18,21] (2 studies each), as well as 1 genome-wide association study (GWAS) [30]. Figure 5 shows the relevant distribution of studies by source of data. ...
Neuroendocrine neoplasms (NENs) and tumors (NETs) are rare neoplasms that may affect any part of the gastrointestinal system. In this scoping review, we attempt to map existing evidence on the role of artificial intelligence, machine learning and deep learning in the diagnosis and management of NENs of the gastrointestinal system. After implementation of inclusion and exclusion criteria, we retrieved 44 studies with 53 outcome analyses. We then classified the papers according to the type of studied NET (26 Pan-NETs, 59.1%; 3 metastatic liver NETs (6.8%), 2 small intestinal NETs, 4.5%; colorectal, rectal, non-specified gastroenteropancreatic and non-specified gastrointestinal NETs had from 1 study each, 2.3%). The most frequently used AI algorithms were Supporting Vector Classification/Machine (14 analyses, 29.8%), Convolutional Neural Network and Random Forest (10 analyses each, 21.3%), Random Forest (9 analyses, 19.1%), Logistic Regression (8 analyses, 17.0%), and Decision Tree (6 analyses, 12.8%). There was high heterogeneity on the description of the prediction model, structure of datasets, and performance metrics, whereas the majority of studies did not report any external validation set. Future studies should aim at incorporating a uniform structure in accordance with existing guidelines for purposes of reproducibility and research quality, which are prerequisites for integration into clinical practice.
... Introduction of wild type RBM47 in brain and lung metastatic derivatives of triple-negative breast cancer cells (MDA-MB-231) inhibited colonization and extended metastasis-free survival in mice, whereas RBM47 I281fs expression failed to reciprocate these effects, suggesting wild type RBM47 to suppress breast cancer progression [18]. Several studies subsequently reported the dysregulation of RBM47 and its correlation with poor prognosis across other tumor types [57][58][59][60][61][62][63][64]. As mentioned previously, spontaneous development of intestinal and colonic polyps in intestine-specific Rbm47 knockout mouse model further resonates with the importance of RBM47 in maintenance of cellular growth and homeostasis in other mammalian species. ...
... uk/ cosmic) describes > 1300 somatic mutations from various human cancer types. A frameshift mutation RBM47 I281fs that generates a truncated, inactive RBM47 protein in triple-negative breast cancer [18]; hypermethylation of RBM47 promoter [62] and miRNA mediated downregulation of RBM47 [58] are distinct mechanisms leading to the loss of optimal RBM47 activity, as is a novel RBM47-CDK12 gene fusion [64]. Validation of the other RBM47 mutations in corresponding cancer types will further illuminate its importance in pan-cancer pathology. ...
RNA-binding proteins (RBPs) are critical players in the post-transcriptional regulation of gene expression and are associated with each event in RNA metabolism. The term ‘RNA-binding motif’ (RBM) is assigned to novel RBPs with one or more RNA recognition motif (RRM) domains that are mainly involved in the nuclear processing of RNAs. RBM47 is a novel RBP conserved in vertebrates with three RRM domains whose contributions to various aspects of cellular functions are as yet emerging. Loss of RBM47 function affects head morphogenesis in zebrafish embryos and leads to perinatal lethality in mouse embryos, thereby assigning it to be an essential gene in early development of vertebrates. Its function as an essential cofactor for APOBEC1 in C to U RNA editing of several targets through substitution for A1CF in the A1CF-APOBEC1 editosome, established a new paradigm in the field. Recent advances in the understanding of its involvement in cancer progression assigned RBM47 to be a tumor suppressor that acts by inhibiting EMT and Wnt/\upbeta-catenin signaling through post-transcriptional regulation. RBM47 is also required to maintain immune homeostasis, which adds another facet to its regulatory role in cellular functions. Here, we review the emerging roles of RBM47 in various biological contexts and discuss the current gaps in our knowledge alongside future perspectives for the field.
... The management of advanced PNETs in VHL should generally follow therapy paradigms for sporadic PNETs. 15,62 It is important to note that the unique genetic profile of VHL-related neoplasms 63 suggests a distinct response to interventions in comparison with non-VHL related neuroendocrine tumors, including sporadic and MEN1-related tumors, and this should be taken into consideration when one is weighing the optimal regimen. ...
Von Hippel–Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018‐2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL‐related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL‐related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL‐related pancreatic manifestations.
... In islet cells, loss of MEN1 enhances proliferation by accelerating S-phase entry [53]. Recently, a genome-wide CpG methylation profiling study showed MEN1-associated pNETs have a higher rate of hypermethylated CpG sites compared to VHL-or other pNET types, indicating menin contributes significantly to the epigenetic control of DNA methylation [54]. ...
Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.
... Rokavec et al. found that RBM47 protein expression was higher in normal colonic mucosa than in adjacent tumor tissue in the majority of cases [30]. The hypermethylation of the promoter of RBM47 had been detected in nonfunctioning pancreatic neuroendocrine tumors [32]. We also found that CBLN2 and TMEM220 expression were down-regulated and SLCO4C1 expression was up-regulated in SW480 cells with RBM47 knockdown, which suggested that CBLN2, SLCO4C1, and TMEM220 were involved in the development of COAD under the regulation of RBM47. ...
Evidence suggests that abnormal DNA methylation patterns play a crucial role in the etiology and pathogenesis of colon adenocarcinoma (COAD). In this study, we identified a total of 97 methylation-driven genes (MDGs) through a comprehensive analysis of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression analysis identified four MDGs (CBLN2, RBM47, SLCO4C1, and TMEM220) associated with overall survival (OS) in COAD patients. A risk prediction model was then developed based on these four MDGs to predict the prognosis of COAD patients. We also created a nomogram that incorporated risk scores, age, and TNM stage to promote a personalized prediction of OS in COAD patients. Compared with the traditional TNM staging system, our new nomogram was better at predicting the OS of COAD patients. In cell experiments, we confirmed that the mRNA expression levels of CLBN2 and TMEM220 were regulated by the methylation of their promoter regions. Moreover, immunohistochemistry showed that CBLN2 and TMEM220 were potential prognostic biomarkers for COAD patients. In summary, we have established a risk prediction model and nomogram that might be effectively utilized to promote the prediction of OS in COAD patients.
