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Zhang K. Molecular Classification and Characterization of Noninsulinoma: Ready for Prime Time in Clinical Practice? Int J Surg Pathol 2025:10668969251327748. [PMID: 40156271 DOI: 10.1177/10668969251327748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Pancreatic neuroendocrine tumors are a heterogeneous group of rare clinical tumors, which can be classified into functional pancreatic neuroendocrine tumor (insulinoma is the most common) and noninsulinoma. Insulinoma and noninsulinoma have different mutation profiles. In noninsulinoma, ATRX/DAXX mutation is associated with alternative lengthening of telomeres-positive phenotype and positively correlated with poor prognosis. Copy number variation is also a prognostic marker for a high risk of recurrence. Scholars have used epigenetics as well as a multiomics approach (combining epigenetics, metabolomics, proteomics, etc) to molecularly type noninsulinoma, and there are huge differences in molecular expression and patient prognosis between different groups. In this manuscript, we summarize the published studies that utilized genome, epigenome, transcriptome, and proteome data to classify noninsulinoma.
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Affiliation(s)
- Kaijian Zhang
- Pathology Department, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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2
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Jiang H, Zhang W, Xu X, Yu X, Ji S. Decoding the genetic puzzle: Mutations in key driver genes of pancreatic neuroendocrine tumors. Biochim Biophys Acta Rev Cancer 2025; 1880:189305. [PMID: 40158667 DOI: 10.1016/j.bbcan.2025.189305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 03/23/2025] [Accepted: 03/24/2025] [Indexed: 04/02/2025]
Abstract
Although pancreatic neuroendocrine tumors (PanNETs) are less common than other pancreatic tumors, they show significant differences in clinical behavior, genetics, and treatment responses. The understanding of the molecular pathways of PanNETs has gradually improved with advances in sequencing technology. Mutations in MEN1 (the most frequently varied gene) may result in the deletion of the tumor suppressor menin, affecting gene regulation, DNA repair, and chromatin modification. Changes in ATRX and DAXX involve chromatin remodeling, telomere stability and are associated with the alternative lengthening of telomeres (ALT) pathway and aggressive tumors. VHL mutations emphasize the roles of hypoxia and angiogenesis. Mutations in PTEN, TSC1/TSC2, and AKT1-3 often disrupt the mTOR pathway, complicating the genetic landscape of PanNETs. Understanding these genetic alterations and their impact on the PI3K/AKT/mTOR axis help to investigate new targeted therapies, which in turn can improve patient prognosis. This review aims to clarify PanNET pathogenesis through key mutations and their clinical relevance.
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Affiliation(s)
- Huanchang Jiang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wuhu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
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3
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McMurry HS, Rivero JD, Chen EY, Kardosh A, Lopez CD, Pegna GJ. Gastroenteropancreatic neuroendocrine tumors: Epigenetic landscape and clinical implications. Curr Probl Cancer 2024; 52:101131. [PMID: 39173542 DOI: 10.1016/j.currproblcancer.2024.101131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/22/2024] [Indexed: 08/24/2024]
Abstract
Neuroendocrine tumors (NETs) are a rare, heterogenous group of neoplasms arising from cells of the neuroendocrine system. Amongst solid tumor malignancies, NETs are notable for overall genetic stability and recent data supports the notion that epigenetic changes may drive NET pathogenesis. In this review, major epigenetic mechanisms of NET pathogenesis are reviewed, including changes in DNA methylation, histone modification, chromatin remodeling, and microRNA. Prognostic implications of the above are discussed, as well as the expanding diagnostic utility of epigenetic markers in NETs. Lastly, preclinical and clinical evaluations of epigenetically targeted therapies in NETs and are reviewed, with a focus on future directions in therapeutic advancement.
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Affiliation(s)
- Hannah S McMurry
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Emerson Y Chen
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Adel Kardosh
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Charles D Lopez
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Guillaume J Pegna
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States.
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Zhu T, Tong H, Du Z, Beck S, Teschendorff AE. An improved epigenetic counter to track mitotic age in normal and precancerous tissues. Nat Commun 2024; 15:4211. [PMID: 38760334 PMCID: PMC11101651 DOI: 10.1038/s41467-024-48649-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 05/09/2024] [Indexed: 05/19/2024] Open
Abstract
The cumulative number of stem cell divisions in a tissue, known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is underexplored and their potential for cancer risk prediction in normal tissues remains to be demonstrated. Here we build and validate an improved pan-tissue DNAm counter of total mitotic age called stemTOC. We demonstrate that stemTOC's mitotic age proxy increases with the tumor cell-of-origin fraction in each of 15 cancer-types, in precancerous lesions, and in normal tissues exposed to major cancer risk factors. Extensive benchmarking against 6 other mitotic counters shows that stemTOC compares favorably, specially in the preinvasive and normal-tissue contexts. By cross-correlating stemTOC to two clock-like somatic mutational signatures, we confirm the mitotic-like nature of only one of these. Our data points towards DNAm as a promising molecular substrate for detecting mitotic-age increases in normal tissues and precancerous lesions, and hence for developing cancer-risk prediction strategies.
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Affiliation(s)
- Tianyu Zhu
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Huige Tong
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Zhaozhen Du
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Stephan Beck
- Medical Genomics Group, UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT, London, UK
| | - Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
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Jiang Y, Dong YH, Zhao SW, Liu DY, Zhang JY, Xu XY, Chen H, Chen H, Jin JB. Multiregion WES of metastatic pancreatic neuroendocrine tumors revealed heterogeneity in genomic alterations, immune microenvironment and evolutionary patterns. Cell Commun Signal 2024; 22:164. [PMID: 38448900 PMCID: PMC10916270 DOI: 10.1186/s12964-024-01545-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/25/2024] [Indexed: 03/08/2024] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs), though uncommon, have a high likelihood of spreading to other body parts. Previously, the genetic diversity and evolutionary patterns in metastatic PanNETs were not well understood. To investigate this, we performed multiregion sampling whole-exome sequencing (MRS-WES) on samples from 10 patients who had not received prior treatment for metastatic PanNETs. This included 29 primary tumor samples, 31 lymph node metastases, and 15 liver metastases. We used the MSK-MET dataset for survival analysis and validation of our findings. Our research indicates that mutations in the MEN1/DAXX genes might trigger the early stages of PanNET development. We categorized the patients based on the presence (MEN1/DAXXmut, n = 7) or absence (MEN1/DAXXwild, n = 3) of these mutations. Notable differences were observed between the two groups in terms of genetic alterations and clinically relevant mutations, confirmed using the MSK-MET dataset. Notably, patients with mutations in MEN1/DAXX/ATRX genes had a significantly longer median overall survival compared to those without these mutations (median not reached vs. 43.63 months, p = 0.047). Multiplex immunohistochemistry (mIHC) analysis showed a more prominent immunosuppressive environment in metastatic tumors, especially in patients with MEN1/DAXX mutations. These findings imply that MEN1/DAXX mutations lead PanNETs through a unique evolutionary path. The disease's progression pattern indicates that PanNETs can spread early, even before clinical detection, highlighting the importance of identifying biomarkers related to metastasis to guide personalized treatment strategies.
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Affiliation(s)
- Yu Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijn 2nd Road, Shanghai, 200025, People's Republic of China
| | - Yi-Han Dong
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Shi-Wei Zhao
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijn 2nd Road, Shanghai, 200025, People's Republic of China
| | - Dong-Yu Liu
- Department of Clinical and Translational Medicine, 3D Medicines Inc., Shanghai, 201114, People's Republic of China
| | - Ji-Yang Zhang
- Department of Clinical and Translational Medicine, 3D Medicines Inc., Shanghai, 201114, People's Republic of China
| | - Xiao-Ya Xu
- Department of Clinical and Translational Medicine, 3D Medicines Inc., Shanghai, 201114, People's Republic of China
| | - Hao Chen
- Bioinformatics Department, JMDNA Inc., Building 23, 500 Furonghua Road, Shanghai, 201203, People's Republic of China.
| | - Hao Chen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijn 2nd Road, Shanghai, 200025, People's Republic of China.
| | - Jia-Bin Jin
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijn 2nd Road, Shanghai, 200025, People's Republic of China.
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Mestre-Alagarda C, Srirajaskanthan R, Zen Y, Giwa M, Howard M, Ooft ML. Genetic and epigenetic prognosticators of neuroendocrine tumours of the GI tract, liver, biliary tract and pancreas: A systematic review and meta-analysis. Histopathology 2024; 84:255-265. [PMID: 37565289 DOI: 10.1111/his.15025] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/25/2023] [Accepted: 07/30/2023] [Indexed: 08/12/2023]
Abstract
Multiple recurrent genetic and epigenetic aberrations have been associated with worse prognosis in multiple studies of neuroendocrine tumours (NETs), but these have been mainly small cohorts and univariate analysis. This review and meta-analysis will focus upon the literature available on NETs of the gastrointestinal (GI) tract, liver, biliary tract and pancreas. PubMed and Embase were searched for publications that investigated the prognostic value of (epi)genetic changes of neuroendocrine tumours. A meta-analysis was performed assessing the association of the (epi)genetic alterations with overall survival (OS), disease-free survival (DFS) or locoregional control (LRC). In the pancreas DAXX/ATRX [hazard ratio (HR) = 3.29; 95% confidence interval (CI) = 2.28-4.74] and alternative lengthening telomeres (ALT) activation (HR = 8.20; 95% CI = 1.40-48.07) showed a pooled worse survival. In the small bowel NETs gains on chromosome 14 were associated with worse survival (HR 2.85; 95% CI = 1.40-5.81). NETs from different anatomical locations must be regarded as different biological entities with diverging molecular prognosticators, and epigenetic changes being important to the pathogenesis of these tumours. This review underpins the prognostic drivers of pancreatic NET which lie in mutations of DAXX/ATRX and ALT pathways. However, there is reaffirmation that prognostic molecular biomarkers of small bowel NETs should be sought in copy number variations (CNVs) rather than in single nucleotide variations (SNVs). This review also reveals how little is known about the prognostic significance of epigenetics in NETs.
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Affiliation(s)
| | | | - Yoh Zen
- Institute of Liver Studies, King's College Hospital and King's College London, London, UK
| | - Mojisola Giwa
- Department of Histopathology, King's College Hospital, King's College, London, UK
| | - Mark Howard
- Department of Histopathology, King's College Hospital, King's College, London, UK
| | - Marc Lucas Ooft
- Institute of Liver Studies, King's College Hospital, London, UK
- Pathology-DNA, Rijnstate Hospital, Arnhem, the Netherlands
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Ragusa D, Vagnarelli P. Contribution of histone variants to aneuploidy: a cancer perspective. Front Genet 2023; 14:1290903. [PMID: 38075697 PMCID: PMC10702394 DOI: 10.3389/fgene.2023.1290903] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/27/2023] [Indexed: 07/29/2024] Open
Abstract
Histone variants, which generally differ in few amino acid residues, can replace core histones (H1, H2A, H2B, and H3) to confer specific structural and functional features to regulate cellular functions. In addition to their role in DNA packaging, histones modulate key processes such as gene expression regulation and chromosome segregation, which are frequently dysregulated in cancer cells. During the years, histones variants have gained significant attention as gatekeepers of chromosome stability, raising interest in understanding how structural and functional alterations can contribute to tumourigenesis. Beside the well-established role of the histone H3 variant CENP-A in centromere specification and maintenance, a growing body of literature has described mutations, aberrant expression patterns and post-translational modifications of a variety of histone variants in several cancers, also coining the term "oncohistones." At the molecular level, mechanistic studies have been dissecting the biological mechanisms behind histones and missegregation events, with the potential to uncover novel clinically-relevant targets. In this review, we focus on the current understanding and highlight knowledge gaps of the contribution of histone variants to aneuploidy, and we have compiled a database (HistoPloidyDB) of histone gene alterations linked to aneuploidy in cancers of the The Cancer Genome Atlas project.
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Affiliation(s)
- Denise Ragusa
- College of Health, Medicine and Life Sciences, Department of Life Sciences, Brunel University London, London, United Kingdom
| | - Paola Vagnarelli
- College of Health, Medicine and Life Sciences, Department of Life Sciences, Brunel University London, London, United Kingdom
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Pergaris A, Genaris I, Stergiou IE, Klijanienko J, Papadakos SP, Theocharis S. The Clinical Impact of Death Domain-Associated Protein and Holliday Junction Recognition Protein Expression in Cancer: Unmasking the Driving Forces of Neoplasia. Cancers (Basel) 2023; 15:5165. [PMID: 37958340 PMCID: PMC10650673 DOI: 10.3390/cancers15215165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/22/2023] [Accepted: 10/24/2023] [Indexed: 11/15/2023] Open
Abstract
Death domain-associated protein (DAXX) and Holliday junction recognition protein (HJURP) act as chaperones of H3 histone variants H3.3 and centromere protein A (CENPA), respectively, and are implicated in many physiological processes, including aging and epigenetic regulation, by controlling various genes' transcription and subsequently protein expression. Research has highlighted both these biomolecules as participants in key procedures of tumorigenesis, including cell proliferation, chromosome instability, and oncogene expression. As cancer continues to exert a heavy impact on patients' well-being and bears substantial socioeconomic ramifications, the discovery of novel biomarkers for timely disease detection, estimation of prognosis, and therapy monitoring remains of utmost importance. In the present review, we present data reported from studies investigating DAXX and HJURP expression, either on mRNA or protein level, in human tissue samples from various types of neoplasia. Of note, the expression of DAXX and HJURP has been associated with a multitude of clinicopathological parameters, including disease stage, tumor grade, patients' overall and disease-free survival, as well as lymphovascular invasion. The data reveal the tumor-promoting properties of DAXX and HJURP in a number of organs as well as their potential use as diagnostic biomarkers and underline the important association between aberrations in their expression and patients' prognosis, rendering them as possible targets of future, personalized and precise therapeutic interventions.
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Affiliation(s)
- Alexandros Pergaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece; (A.P.); (I.G.); (S.P.P.)
| | - Ioannis Genaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece; (A.P.); (I.G.); (S.P.P.)
| | - Ioanna E. Stergiou
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | | | - Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece; (A.P.); (I.G.); (S.P.P.)
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece; (A.P.); (I.G.); (S.P.P.)
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Angelousi A, Koumarianou A, Chatzellis E, Kaltsas G. Resistance of neuroendocrine tumours to somatostatin analogs. Expert Rev Endocrinol Metab 2023; 18:33-52. [PMID: 36651768 DOI: 10.1080/17446651.2023.2166488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
INTRODUCTION A common feature shared by most neuroendocrine tumors (NETs) is the expression on their surface of somatostatin receptors (SSTRs) that are essential for their pathophysiological regulation, diagnosis, and management. The first-generation synthetic somatostatin analogs (SSAs), octreotide and lanreotide, constitute the cornerstone of treatment for growth hormone secreting pituitary adenomas and functioning, progressive functioning, and non-functioning gastro-entero-pancreatic (GEP-NETs). SSAs exert their mechanism of action through binding to the SSTRs; however, their therapeutic response is frequently attenuated or diminished by the development of resistance. The phenomenon of resistance is complex implicating the presence of additional epigenetic and genetic mechanisms. AREAS COVERED We aim to analyze the molecular, genetic, and epigenetic mechanisms of resistance to SSA treatment. We also summarize recent clinical data related to the development of resistance on conventional and non-conventional modes of administration of the first-generation SSAs and the second-generation SSA pasireotide. We explore mechanisms used to counteract the resistance to SSAs using higher doses or more frequent mode of administration of SSAs and/or combination treatments. EXPERT OPINION There is considerable heterogeneity in the development of resistance to SSAs that is tumor-specific necessitating the delineation of the underlying pathophysiological processes to further expand their therapeutic applications.
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Affiliation(s)
- Anna Angelousi
- First Department of Internal Medicine, Unit of Endocrinology, Laikon General hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Koumarianou
- Hematology Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftherios Chatzellis
- Endocrinology Diabetes and Metabolism Department, 251 Hellenic Air Force and VA General Hospital, Athens, Greece
| | - Gregory Kaltsas
- First Propaedeutic Department of Internal Medicine, Endocrine Unit, National and Kapodistrian University of Athens, Athens, Greece
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Insights into Epigenetic Changes Related to Genetic Variants and Cells-of-Origin of Pancreatic Neuroendocrine Tumors: An Algorithm for Practical Workup. Cancers (Basel) 2022; 14:cancers14184444. [PMID: 36139607 PMCID: PMC9496769 DOI: 10.3390/cancers14184444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Pancreatic neuroendocrine tumors are composite entities due to their heterogeneity illustrated in clinical behavior, mutational pattern, and site of origin. Pancreatic neuroendocrine tumors display a low mutation burden with frequently epigenetic alterations, such as histone modifications, chromatin remodeling, or DNA methylation status. Using the epigenomic data of the pancreatic neuroendocrine tumors converged to the identification of molecularly distinct subgroups. Furthermore, epigenetic signatures could be used as biomarkers due to their link to cell lineages and genetic driver mutations. We integrated the current knowledge on genetic and epigenetic alterations involved in endocrine lineage associated with these neoplasms to present a pathway-based overview. In this review, we suggest a simplified algorithm on how to manage pancreatic neuroendocrine tumors from a practical perspective based on pathologist ’analysis. Abstract 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.
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Hackeng WM, Assi HA, Westerbeke FHM, Brosens LAA, Heaphy CM. Prognostic and Predictive Biomarkers for Pancreatic Neuroendocrine Tumors. Surg Pathol Clin 2022; 15:541-554. [PMID: 36049835 DOI: 10.1016/j.path.2022.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Pancreatic neuroendocrine tumors (PanNETs) represent a clinically challenging disease because these tumors vary in clinical presentation, natural history, and prognosis. Novel prognostic biomarkers are needed to improve patient stratification and treatment options. Several putative prognostic and/or predictive biomarkers (eg, alternative lengthening of telomeres, alpha-thalassemia/mental retardation, X-linked (ATRX)/Death Domain Associated Protein (DAXX) loss) have been independently validated. Additionally, recent transcriptomic and epigenetic studies focusing on endocrine differentiation have identified PanNET subtypes that display similarities to either α-cells or β-cells and differ in clinical outcomes. Thus, future prospective studies that incorporate genomic and epigenetic biomarkers are warranted and have translational potential for individualized therapeutic and surveillance strategies.
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Affiliation(s)
- Wenzel M Hackeng
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Hussein A Assi
- Department of Medicine, Boston University School of Medicine, 820 Harrison Avenue, FGH 2011, Boston, MA 02118, USA
| | - Florine H M Westerbeke
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Christopher M Heaphy
- Department of Medicine, Boston University School of Medicine, 650 Albany Street, Room 444, Boston, MA 02118, USA; Department of Pathology & Laboratory Medicine, Boston University School of Medicine, 650 Albany Street, Room 444, Boston, MA 02118, USA.
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12
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Diagnosis in Neuroendocrine Neoplasms: From Molecular Biology to Molecular Imaging. Cancers (Basel) 2022; 14:cancers14102514. [PMID: 35626118 PMCID: PMC9139608 DOI: 10.3390/cancers14102514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Neuroendocrine neoplasms are a small group of malignancies with a diverse prognosis and behaviour. In order to offer an adequate treatment, physicians need to perform a proper diagnosis, staging and stratification. This review aims to help to integrate the information from pathology, immunohistochemistry, molecular biology and imaging to guide this process. Abstract Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours with a diverse behaviour, biology and prognosis, whose incidence is gradually increasing. Their diagnosis is challenging and a multidisciplinary approach is often required. The combination of pathology, molecular biomarkers, and the use of novel imaging techniques leads to an accurate diagnosis and a better treatment approach. To determine the functionality of the tumour, somatostatin receptor expression, differentiation, and primary tumour origin are the main determining tumour-dependent factors to guide treatment, both in local and metastatic stages. Until recently, little was known about the biological behaviour of these tumours. However, in recent years, many advances have been achieved in the molecular characterization and diagnosis of NENs. The incorporation of novel radiotracer-based imaging techniques, such as 68Gallium-DOTATATE PET-CT, has significantly increased diagnostic sensitivity, while introducing the theragnosis concept, offering new treatment strategies. Here, we will review current knowledge and novelties in the diagnosis of NENs, including molecular biology, pathology, and new radiotracers.
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Zhu T, Liu J, Beck S, Pan S, Capper D, Lechner M, Thirlwell C, Breeze CE, Teschendorff AE. A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution. Nat Methods 2022; 19:296-306. [PMID: 35277705 PMCID: PMC8916958 DOI: 10.1038/s41592-022-01412-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 01/28/2022] [Indexed: 02/07/2023]
Abstract
Bulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data. This resource presents an in silico generated DNA methylation atlas that can be used for cell-type deconvolution of human tissues.
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Dreijerink KM, Hackeng WM, Singhi AD, Heaphy CM, Brosens LA. Clinical implications of cell-of-origin epigenetic characteristics in non-functional pancreatic neuroendocrine tumors. J Pathol 2022; 256:143-148. [PMID: 34750813 DOI: 10.1002/path.5834] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/03/2021] [Indexed: 02/05/2023]
Abstract
Primary non-functional pancreatic neuroendocrine tumors (NF-PanNETs) are a heterogeneous group of neuroendocrine neoplasms that display highly variable clinical behavior. Therefore, NF-PanNETs often present clinical teams with a dilemma: the uncertain metastatic potential of the tumor has to be weighed against the morbidity associated with surgical resection. Thus, rather than utilizing current radiologic thresholds, there is an urgent need for improved prognostic biomarkers. Recent studies aimed at understanding the epigenetic underpinnings of NF-PanNETs have led to the identification of tumor subgroups based on histone modification and DNA methylation patterns. These molecular profiles tend to resemble the cellular origins of PanNETs. Subsequent retrospective analyses have demonstrated that these molecular signatures are of prognostic value and, importantly, may be useful in the preoperative setting. These studies have highlighted that sporadic NF-PanNETs displaying biomarkers associated with disease progression and poor prognosis, such as alternative lengthening of telomeres, inactivating alpha thalassemia/mental retardation X-linked (ATRX) or death domain-associated protein (DAXX) gene mutations, or copy number variations, more often display alpha cell characteristics. Conversely, NF-PanNETs with beta cell characteristics often lack these unfavorable biomarkers. Alternative lengthening of telomeres, transcription factor protein expression, and possibly DNA methylation can be assessed in endoscopic ultrasound-guided tumor biopsies. Prospective studies focusing on cell-of-origin and epigenetic profile-driven decision making prior to surgery are likely to be routinely implemented into clinical practice in the near future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Koen Ma Dreijerink
- Amsterdam Center for Endocrine and Neuroendocrine Tumors, Department of Endocrinology, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands
| | - Wenzel M Hackeng
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Christopher M Heaphy
- Departments of Medicine and Pathology & Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Lodewijk Aa Brosens
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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Konukiewitz B, Jesinghaus M, Kasajima A, Klöppel G. Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls. Virchows Arch 2021; 480:247-257. [PMID: 34647171 PMCID: PMC8986719 DOI: 10.1007/s00428-021-03211-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/06/2021] [Accepted: 09/21/2021] [Indexed: 12/29/2022]
Abstract
Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.
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Affiliation(s)
- Björn Konukiewitz
- Institute of Pathology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität zu Kiel, Arnold-Heller-Straße 3/14, 24105, Kiel, Germany.
| | - Moritz Jesinghaus
- Institute of Pathology, Universitätsklinikum Marburg, Baldingerstraße, 35043, Marburg, Germany
| | - Atsuko Kasajima
- Institute of Pathology, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
| | - Günter Klöppel
- Institute of Pathology, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
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16
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Heaphy CM, VandenBussche CJ. Prognostic biomarkers in pancreatic neuroendocrine tumors. Cancer Cytopathol 2021; 129:841-843. [PMID: 34242496 DOI: 10.1002/cncy.22457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 05/10/2021] [Indexed: 11/10/2022]
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Wang F, Xu X, Ye Z, Qin Y, Yu X, Ji S. Prognostic Significance of Altered ATRX/DAXX Gene in Pancreatic Neuroendocrine Tumors: A Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:691557. [PMID: 34220718 PMCID: PMC8253224 DOI: 10.3389/fendo.2021.691557] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/31/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing recently has shown very frequent somatic mutations in the alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes in PanNETs. And the prognostic significance of altered ATRX/DAXX genes in PanNETs patients have been revealed in several reports. However, many of these include small sample size and hold controversial opinions. To increase statistical power, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of altered ATRX/DAXX genes mainly on overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) in PanNETs. METHODS Eligible studies were identified and quality was assessed using multiple search strategies (last search May 2021). Data were collected from studies about prognostic significance of altered ATRX/DAXX in PanNETs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations. RESULTS Fourteen studies involving 2313 patients treated for PanNETs were included. After evaluating for publication bias, disease-free survival and relapse-free survival was significantly shortened in patients with altered ATRX/DAXX gene, with combined HR 5.05 (95% confidence interval (CI): 1.58-16.20, P = 0.01) and 3.21 (95% confidence interval (CI): 1.44-7.16, P < 0.01) respectively. However, the combined data showed there were no difference between patients with altered ATRX/DAXX gene or not in overall survival, with a combined HR 0.71 (95% confidence interval (CI): 0.44-1.15, P = 0.23). We also performed a subgroup analysis with metastatic patients in overall survival, showing a combined HR 0.22 (95% confidence interval (CI): 0.11-0.48, P = 0.96). The small number of studies and paucity of multivariate analyses are the limitations of our study. CONCLUSIONS This is the first rigorous pooled analysis assessing ATRX/DAXX mutation as prognostic biomarkers in PanNETs. Patients with altered ATRX/DAXX gene would have poor DFS according to the combined data. And altered ATRX/DAXX genes in metastatic patients showed a trend towards improved overall survival, although the difference did not reach statistical significance.
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Affiliation(s)
- Fei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zeng Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Metastatic Timing and Genetic Heterogeneity in the Evolution of a Pancreatic Neuroendocrine Tumor. Am J Gastroenterol 2021; 116:844-847. [PMID: 33982971 DOI: 10.14309/ajg.0000000000001004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Di Domenico A, Pipinikas CP, Maire RS, Bräutigam K, Simillion C, Dettmer MS, Vassella E, Thirlwell C, Perren A, Marinoni I. Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression. Commun Biol 2020; 3:740. [PMID: 33288854 PMCID: PMC7721725 DOI: 10.1038/s42003-020-01479-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. In the current study we examine whether tumour DNA methylation (DNAme) profiling combined with genomic data is able to identify cell of origin and to reveal pathways involved in PanNET progression. We analyse genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confirm cell identity, we investigate ARX and PDX1 expression. Based on epigenetic similarities, PanNETs cluster in α-like, β-like and intermediate tumours. The epigenetic similarity to α-cells progressively decreases in the intermediate tumours, which present unclear differentiation. Specific transcription factor methylation and expression vary in the respective α/β-tumour groups. Depending on DNAme similarity to α/β-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.
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Affiliation(s)
- Annunziata Di Domenico
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010, Bern, Switzerland
| | | | - Renaud S Maire
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
| | - Konstantin Bräutigam
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
| | - Cedric Simillion
- Bioinformatics and Computational Biology, University of Bern, Baltzerstrasse 6, 3012, Bern, Switzerland
| | - Matthias S Dettmer
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
| | - Erik Vassella
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
| | - Chrissie Thirlwell
- UCL Cancer Institute, 72, Huntley Street, London, WC1E 6JD, UK
- University of Exeter, College of Medicine and Health, St Luke's Campus, Heavitree Road, Exeter, EX1 2LU, UK
| | - Aurel Perren
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland
| | - Ilaria Marinoni
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland.
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20
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Jiang R, Hong X, Zhao Y, Wu W. Application of multiomics sequencing and advances in the molecular mechanisms of pancreatic neuroendocrine neoplasms. Cancer Lett 2020; 499:39-48. [PMID: 33246093 DOI: 10.1016/j.canlet.2020.11.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/10/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022]
Abstract
The incidence of pancreatic neuroendocrine neoplasms (PanNENs) has gradually increased. PanNENs comprise two subtypes with different clinical manifestations and molecular mechanisms: functional PanNENs and nonfunctional PanNENs. Excessive hormones and tumor progression severely affect the quality of life of patients or are even life threatening. However, the molecular mechanisms of hormone secretion and tumor progression in PanNENs have not yet been fully elucidated. At present, advancements in sequencing technologies have led to the exploration of new biological markers and an advanced understanding of molecular mechanisms in PanNENs. Multiomics sequencing could reveal differences and similarities in molecular features in different fields. However, sequencing studies of PanNENs are booming and should be summarized to integrate the current findings. In this review, we summarize the current status of multiomics sequencing in PanNENs to further guide its application. We explore mainly advancements in the genome, transcriptome, and DNA methylation fields. In addition, the cell origin of PanNENs, which has been a hot issue in sequencing research, is described in multiple fields.
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Affiliation(s)
- Rui Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Xiafei Hong
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
| | - Wenming Wu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
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21
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Telomere length alterations and ATRX/DAXX loss in pituitary adenomas. Mod Pathol 2020; 33:1475-1481. [PMID: 32203094 PMCID: PMC8867890 DOI: 10.1038/s41379-020-0523-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 03/05/2020] [Accepted: 03/05/2020] [Indexed: 01/03/2023]
Abstract
Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.
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Horton TM, Sundaram V, Lee CHJ, Hornbacker K, Van Vleck A, Benjamin KN, Zemek A, Longacre TA, Kunz PL, Annes JP. PAM staining intensity of primary neuroendocrine neoplasms is a potential prognostic biomarker. Sci Rep 2020; 10:10943. [PMID: 32616904 PMCID: PMC7331689 DOI: 10.1038/s41598-020-68071-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are rare epithelial tumors with heterogeneous and frequently unpredictable clinical behavior. Available biomarkers are insufficient to guide individual patient prognosis or therapy selection. Peptidylglycine α-amidating monooxygenase (PAM) is an enzyme expressed by neuroendocrine cells that participates in hormone maturation. The objective of this study was to assess the distribution, clinical associations and survival implications of PAM immunoreactivity in primary NENs. Of 109 primary NENs, 7% were PAM-negative, 25% were PAM-low and 68% were PAM-high. Staining intensity was high in small bowel (p = 0.04) and low in stomach (p = 0.004) NENs. PAM staining was lower in higher grade tumors (p < 0.001) and patients who died (p < 0.001) but did not vary by tumor size or stage at surgery. In patients who died, time to death was shorter in patients with reduced PAM immunoreactivity: median times to death were 11.3 (PAM-negative), 29.4 (PAM-low) and 61.7 (PAM-high) months. Lower PAM staining was associated with increased risk of death after adjusting for disease stage [PAM negative, HR = 13.8 (CI: 4.2–45.5)]. PAM immunoreactivity in primary NENs is readily assessable and a potentially useful stage-independent predictor of survival.
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Affiliation(s)
- Timothy M Horton
- Department of Chemistry, Stanford University, Stanford, CA, USA.,Chemistry, Engineering and Medicine for Human Health (ChEM-H) Institute, Stanford University, Stanford, CA, USA
| | - Vandana Sundaram
- Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Christine Hye-Jin Lee
- Division of Endocrinology, Department of Medicine, Stanford University, CCSR 2255-A, 1291 Welch Rd., Stanford, CA, 94305-5165, USA
| | - Kathleen Hornbacker
- Endocrine Oncology Program, Stanford University, Stanford, USA.,Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Aidan Van Vleck
- Division of Endocrinology, Department of Medicine, Stanford University, CCSR 2255-A, 1291 Welch Rd., Stanford, CA, 94305-5165, USA
| | - Kaisha N Benjamin
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Allison Zemek
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Teri A Longacre
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Pamela L Kunz
- Endocrine Oncology Program, Stanford University, Stanford, USA.,Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Justin P Annes
- Chemistry, Engineering and Medicine for Human Health (ChEM-H) Institute, Stanford University, Stanford, CA, USA. .,Division of Endocrinology, Department of Medicine, Stanford University, CCSR 2255-A, 1291 Welch Rd., Stanford, CA, 94305-5165, USA. .,Endocrine Oncology Program, Stanford University, Stanford, USA.
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Boons G, Vandamme T, Ibrahim J, Roeyen G, Driessen A, Peeters D, Lawrence B, Print C, Peeters M, Van Camp G, Op de Beeck K. PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis. Cancers (Basel) 2020; 12:cancers12061461. [PMID: 32512761 PMCID: PMC7352978 DOI: 10.3390/cancers12061461] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/30/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the PDX1 region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the PDX1 methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], p = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the PDX1 methylation status for the subtyping of PNENs and its prognostic importance.
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Affiliation(s)
- Gitta Boons
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, Belgium; (G.B.); (T.V.); (J.I.); (M.P.); (G.V.C.)
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
| | - Timon Vandamme
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, Belgium; (G.B.); (T.V.); (J.I.); (M.P.); (G.V.C.)
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, 3015GD Rotterdam, The Netherlands
- NETwerk, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Joe Ibrahim
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, Belgium; (G.B.); (T.V.); (J.I.); (M.P.); (G.V.C.)
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
| | - Geert Roeyen
- Department of Hepatobiliary, Endocrine and Transplantation Surgery, Antwerp University Hospital, 2650 Edegem, Belgium;
| | - Ann Driessen
- Department of Pathology, Antwerp University Hospital and University of Antwerp, 2650 Edegem, Belgium;
| | - Dieter Peeters
- Histopathology, Imaging and Quantification Unit, HistoGeneX, 2610 Antwerp, Belgium;
- Department of Pathology, AZ Sint-Maarten, 2800 Mechelen, Belgium
| | - Ben Lawrence
- Discipline of Oncology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland 1023, New Zealand;
- Maurice Wilkins Centre Hosted by the University of Auckland, Auckland 1023, New Zealand;
| | - Cristin Print
- Maurice Wilkins Centre Hosted by the University of Auckland, Auckland 1023, New Zealand;
- Department of Molecular Medicine and Pathology, School of Medical Sciences, Faculty of Medicine and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Marc Peeters
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, Belgium; (G.B.); (T.V.); (J.I.); (M.P.); (G.V.C.)
| | - Guy Van Camp
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, Belgium; (G.B.); (T.V.); (J.I.); (M.P.); (G.V.C.)
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
| | - Ken Op de Beeck
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, Belgium; (G.B.); (T.V.); (J.I.); (M.P.); (G.V.C.)
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
- Correspondence: ; Tel.: +32-3275-97-91
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24
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Sadowski SM, Pieterman CRC, Perrier ND, Triponez F, Valk GD. Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature. Endocr Relat Cancer 2020; 27:R145-R161. [PMID: 32229700 PMCID: PMC7304521 DOI: 10.1530/erc-19-0372] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.
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Affiliation(s)
- S M Sadowski
- Endocrine Surgery, Surgical Oncology Program, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - C R C Pieterman
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - N D Perrier
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - F Triponez
- Thoracic and Endocrine Surgery and Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland
| | - G D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
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25
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Zakka K, Nagy R, Drusbosky L, Akce M, Wu C, Alese OB, El-Rayes BF, Kasi PM, Mody K, Starr J, Shaib WL. Blood-based next-generation sequencing analysis of neuroendocrine neoplasms. Oncotarget 2020; 11:1749-1757. [PMID: 32477464 PMCID: PMC7233805 DOI: 10.18632/oncotarget.27588] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/10/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that span from well-differentiated neuroendocrine tumors (NETs) to highly aggressive neoplasms classified as neuroendocrine carcinomas (NECs). The genomic landscape of NENs has not been well studied. The aim of this study is to confirm the feasibility of next generation sequencing (NGS) testing circulating tumor DNA (ctDNA) in patients with NENs and characterize common alterations in the genomic landscape.
Results: Of the 320 NEN patients, 182 (57%) were male with a median age of 63 years (range: 8-93) years. Tumor type included pancreatic NET (N = 165, 52%), gastrointestinal NEC (N = 52, 16%), large cell lung NEC (N = 21, 7%), nasopharyngeal NEC (N = 16, 5%) and NEC/NET not otherwise specified (N = 64, 20%). ctDNA NGS testing was performed on 338 plasma samples; 14 patients had testing performed twice and 2 patients had testing performed three times. Genomic alterations were defined in 280 (87.5%) samples with a total of 1,012 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Of the 280 samples with alterations, TP53 associated genes were most commonly altered (N = 145, 52%), followed by KRAS (N = 61, 22%), EGFR (N = 33, 12%), PIK3CA (N = 30, 11%), BRAF (N = 28, 10%), MYC (N = 28, 10%), CCNE1 (N = 28, 10%), CDK6 (N = 22, 8%), RB1 (N = 19, 7%), NF1 (N = 19, 7%), MET (N = 19, 7%), FGFR1 (N = 19, 7%), APC (N = 19, 7%), ERBB2 (N = 16, 6%) and PTEN (N = 14, 5%).
Conclusions: Evaluation of ctDNA was feasible among individuals with NEN. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in NEN patients.
Patients and Methods: Molecular alterations in 338 plasma samples from 320 patients with NEN were evaluated using clinical-grade NGS of ctDNA (Guardant360®) across multiple institutions. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes.
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Affiliation(s)
- Katerina Zakka
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | | | | | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Christina Wu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Olatunji B Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Pashtoon Murtaza Kasi
- Department of Hematology and Medical Oncology, University of Iowa, Iowa City, IA, USA
| | - Kabir Mody
- Department of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Jason Starr
- Department of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Walid L Shaib
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
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26
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Starr JS, Sonbol MB, Hobday TJ, Sharma A, Kendi AT, Halfdanarson TR. Peptide Receptor Radionuclide Therapy for the Treatment of Pancreatic Neuroendocrine Tumors: Recent Insights. Onco Targets Ther 2020; 13:3545-3555. [PMID: 32431509 PMCID: PMC7205451 DOI: 10.2147/ott.s202867] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 03/26/2020] [Indexed: 12/27/2022] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) is a paradigm shifting approach to the treatment of neuroendocrine tumors. Although there are no prospective randomized trials directly studying PRRT in pancreatic neuroendocrine tumors (panNETs), there are data to suggest benefit in this patient population. Collectively, the data, consisting of two prospective and six retrospective studies, show a median PFS ranging from 20 to 39 months and a median OS ranging from 37 to 79 months. There are ongoing (and upcoming) prospective, randomized trials of PRRT in panNETs, which will provide further evidence to support this approach.
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Affiliation(s)
- Jason S Starr
- Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA
| | | | - Timothy J Hobday
- Division of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA
| | - Akash Sharma
- Division of Nuclear Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Ayse Tuba Kendi
- Division of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA
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27
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Kit OI, Gvaldin DY, Trifanov VS, Kolesnikov EN, Timoshkina NN. Molecular-Genetic Features of Pancreatic Neuroendocrine Tumors. RUSS J GENET+ 2020. [DOI: 10.1134/s1022795420020064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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28
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Colao A, de Nigris F, Modica R, Napoli C. Clinical Epigenetics of Neuroendocrine Tumors: The Road Ahead. Front Endocrinol (Lausanne) 2020; 11:604341. [PMID: 33384663 PMCID: PMC7770585 DOI: 10.3389/fendo.2020.604341] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/12/2020] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine tumors, or NETs, are cancer originating in neuroendocrine cells. They are mostly found in the gastrointestinal tract or lungs. Functional NETs are characterized by signs and symptoms caused by the oversecretion of hormones and other substances, but most NETs are non-functioning and diagnosis in advanced stages is common. Thus, novel diagnostic and therapeutic strategies are warranted. Epigenetics may contribute to refining the diagnosis, as well as to identify targeted therapy interfering with epigenetic-sensitive pathways. The goal of this review was to discuss the recent advancement in the epigenetic characterization of NETs highlighting their role in clinical findings.
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Affiliation(s)
- Annamaria Colao
- Department of Clinical Medicine and Surgery, Unesco Chair Health Education and Sustainable Development, Federico II University of Naples, Naples, Italy
| | - Filomena de Nigris
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Roberta Modica
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- *Correspondence: Roberta Modica,
| | - Claudio Napoli
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
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29
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Berner AM, Pipinikas C, Ryan A, Dibra H, Moghul I, Webster A, Luong TV, Thirlwell C. Diagnostic Approaches to Neuroendocrine Neoplasms of Unknown Primary Site. Neuroendocrinology 2020; 110:563-573. [PMID: 31658461 DOI: 10.1159/000504370] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/26/2019] [Indexed: 12/18/2022]
Abstract
Neuroendocrine neoplasms (NENs) arise from cells of neuronal and endocrine differentiation. While they are a rare entity, an increasing proportion of patients with NEN present with metastatic disease and no evident primary site using routine imaging or histopathology. NENs of unknown primary site have a poorer prognosis, often due to the challenge of selecting appropriate evidence-based management. We review the available literature and guidelines for the management of NENs of unknown primary site including clinical features, biochemical tests, histopathology, imaging, surgical exploration and localised and systemic treatments. We also discuss novel molecular techniques currently under investigation to aid primary site identification.
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Affiliation(s)
- Alison May Berner
- Department of Tumour Biology, Barts Cancer Institute, London, United Kingdom,
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom,
| | | | - Anna Ryan
- Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, Northwood, United Kingdom
| | | | - Ismail Moghul
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom
| | - Amy Webster
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom
| | - Tu Vinh Luong
- Royal Free Hospitals NHS Trust, London, United Kingdom
| | - Christina Thirlwell
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom
- University of Exeter School of Medicine and Health, RILD Building, Exeter, United Kingdom
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30
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Terra Md SBSP, Xie Md PhD H, Boland Md JM, Mansfield Md AS, Molina Md PhD JR, Roden Md AC. Loss of ATRX expression predicts worse prognosis in pulmonary carcinoid tumors. Hum Pathol 2019; 94:78-85. [PMID: 31499081 DOI: 10.1016/j.humpath.2019.08.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/14/2019] [Accepted: 08/26/2019] [Indexed: 12/15/2022]
Abstract
Loss of alpha thalassemia/mental retardation syndrome X-linked (ATRX), a chromatin regulator, is associated with worse prognosis in pancreatic neuroendocrine tumors. We investigated ATRX expression in pulmonary carcinoid tumors (PCT) and its diagnostic and prognostic role in these patients. Resected PCTs (1997-2017) were reviewed. Tumors were staged according to 8th UICC/AJCC system. ATRX nuclear expression was recorded independently by 2 reviewers. A cutoff of ≤5% of nuclear ATRX expression was statistically established as loss of expression. One-hundred-fifteen patients (72 women [63%]; median age of 60.5 years [interquartile range, 50.8-71.5]) harbored 69 (60%) typical and 46 (40%) atypical PCTs. Median tumor size was 2.3 cm (interquartile range, 1.6-3.8 cm). Loss of ATRX expression was associated with atypical PCTs (OR 7.4 [95% CI, 2.6-23, P < .001]), when adjusted for lymphovascular invasion and perineural invasion. ATRX expression predicted atypical PCT with sensitivity of 37% (95% CI, 24%-52%), specificity of 92% (95% CI, 86%-98%), AUC of 0.62 (95% CI, 0.52-0.72). Loss of ATRX expression was associated with shorter disease-specific survival (HR = 11, 95% CI, 1.8-68, P = .01), after adjusting for lymphovascular invasion and presence of metastatic disease at time of diagnosis. Interobserver agreement on ATRX expression by two reviewers was substantial (κ = 0.72 [95% CI, 0.60-0.80]). ATRX expression is more commonly lost in atypical than in typical PCT, and is associated with more aggressive tumor characteristics and shorter disease-specific survival.
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Affiliation(s)
| | - Hao Xie Md PhD
- Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Jennifer M Boland Md
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Aaron S Mansfield Md
- Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | | | - Anja C Roden Md
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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31
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Boons G, Vandamme T, Peeters M, Van Camp G, Op de Beeck K. Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies. Rev Endocr Metab Disord 2019; 20:333-351. [PMID: 31368038 DOI: 10.1007/s11154-019-09508-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
High-throughput analysis, including next-generation sequencing and microarrays, have strongly improved our understanding of cancer biology. However, genomic data on rare cancer types, such as neuroendocrine neoplasms, has been lagging behind. Neuroendocrine neoplasms (NENs) develop from endocrine cells spread throughout the body and are highly heterogeneous in biological behavior. In this challenging disease, there is an urgent need for new therapies and new diagnostic, prognostic, follow-up and predictive biomarkers to aid patient management. The last decade, molecular data on neuroendocrine neoplasms of the gastrointestinal tract and pancreas, termed gastroenteropancreatic NENs (GEP-NENs), has strongly expanded. The aim of this review is to give an overview of the recent advances on (epi)genetic level and highlight their clinical applications to address the current needs in GEP-NENs. We illustrate how molecular alterations can be and are being used as therapeutic targets, how mutations in DAXX/ATRX and copy number variations could be used as prognostic biomarkers, how far we are in identifying predictive biomarkers and how genetics can contribute to GEP-NEN classification. Finally, we discuss recent studies on liquid biopsies in the field of GEP-NENs and illustrate how liquid biopsies can play a role in patient management. In conclusion, molecular studies have suggested multiple potential biomarkers, but further validation is ongoing.
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Affiliation(s)
- Gitta Boons
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
| | - Timon Vandamme
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015GE, Rotterdam, The Netherlands
| | - Marc Peeters
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Guy Van Camp
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium.
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium.
| | - Ken Op de Beeck
- Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
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32
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Mafficini A, Scarpa A. Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms. Endocr Rev 2019; 40:506-536. [PMID: 30657883 PMCID: PMC6534496 DOI: 10.1210/er.2018-00160] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
Abstract
Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.
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Affiliation(s)
- Andrea Mafficini
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
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33
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Chou A, Itchins M, de Reuver PR, Arena J, Clarkson A, Sheen A, Sioson L, Cheung V, Perren A, Nahm C, Mittal A, Samra JS, Pajic M, Gill AJ. ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors. Hum Pathol 2018; 82:249-257. [PMID: 30081149 DOI: 10.1016/j.humpath.2018.07.032] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/20/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022]
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms accounting for 1% to 2% of all pancreatic tumors. The biological behavior of PanNETs is heterogeneous and unpredictable, adding to the difficulties of clinical management. The DAXX (death domain associated protein) and ATRX (α-thalassemia/mental retardation syndrome X-linked) genes encode proteins involved in SWI/SNF-like chromatin remodeling. Somatic inactivating mutations in DAXX and ATRX are frequent in PanNETs, mutually exclusive, and associated with telomere dysfunction, resulting in genomic instability and alternate lengthening of telomeres. We sought to assess the clinical significance of the loss of the ATRX and DAXX proteins as determined by immunohistochemistry (IHC) in patients with PanNET. From an unselected cohort of 105 patients, we found ATRX loss in 10 tumors (9.5%) and DAXX loss in 16 (15.2%). DAXX and ATRX losses were confirmed mutually exclusive and associated with other adverse clinicopathological variables and poor survival in univariate analysis. In addition, ATRX loss was also associated with higher AJCC stage and infiltrative tumor borders. However, only ATRX loss, lymphovascular invasion, and perineural spread were independent predictors of poor overall survival in multivariate analysis. In conclusion, loss of expression of ATRX as determined by IHC is a useful independent predictor of poor overall survival in PanNETs. Given its relative availability, ATRX loss as determined by IHC may have a role in routine clinical practice to refine prognostication in patients with PanNET.
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Affiliation(s)
- Angela Chou
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; University of Sydney, Sydney, NSW 2006, Australia; Department of Anatomical Pathology, SYDPATH, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia; The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Malinda Itchins
- University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Philip R de Reuver
- Department of Surgery, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Jennifer Arena
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Adele Clarkson
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Amy Sheen
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Loretta Sioson
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Veronica Cheung
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern 3012, Switzerland
| | - Christopher Nahm
- University of Sydney, Sydney, NSW 2006, Australia; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Anubhav Mittal
- University of Sydney, Sydney, NSW 2006, Australia; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Jaswinder S Samra
- University of Sydney, Sydney, NSW 2006, Australia; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Marina Pajic
- The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Anthony J Gill
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; University of Sydney, Sydney, NSW 2006, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
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34
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Amair-Pinedo F, Matos I, Saurí T, Hernando J, Capdevila J. The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors. Target Oncol 2018; 12:757-774. [PMID: 29143176 DOI: 10.1007/s11523-017-0532-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that originate from neuroendocrine stem cells and express both neural and endocrine markers. They are found in almost every organ, and while NENs are mostly associated with slow growth, complications due to the uncontrolled secretion of active peptides, and metastatic disease, may significantly impair the quality of life and can ultimately lead to the death of affected individuals. Expanding knowledge of the genetic, epigenetic, and proteomic landscapes of NENs has led to a better understanding of their molecular pathology and consequently increased treatment options for patients. Here, we review the principal breakthroughs in NEN treatment management, owing largely to omics technologies over the last few years, current recommendations of systemic treatment, and ongoing research into the identification of predictive and response biomarkers based on molecular targeted therapies.
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Affiliation(s)
| | - Ignacio Matos
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Tamara Saurí
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jorge Hernando
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jaume Capdevila
- Vall d'Hebron University Hospital, Barcelona, Spain. .,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
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35
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Aristizabal Prada ET, Auernhammer CJ. Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. Endocr Connect 2018; 7:R1-R25. [PMID: 29146887 PMCID: PMC5754510 DOI: 10.1530/ec-17-0286] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/16/2017] [Indexed: 12/12/2022]
Abstract
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras-Raf-MEK-ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.
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Affiliation(s)
- E T Aristizabal Prada
- Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - C J Auernhammer
- Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
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Bano D, Piazzesi A, Salomoni P, Nicotera P. The histone variant H3.3 claims its place in the crowded scene of epigenetics. Aging (Albany NY) 2017; 9:602-614. [PMID: 28284043 PMCID: PMC5391221 DOI: 10.18632/aging.101194] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 02/26/2017] [Indexed: 12/16/2022]
Abstract
Histones are evolutionarily conserved DNA-binding proteins. As scaffolding molecules, they significantly regulate the DNA packaging into the nucleus of all eukaryotic cells. As docking units, they influence the recruitment of the transcriptional machinery, thus establishing unique gene expression patterns that ultimately promote different biological outcomes. While canonical histones H3.1 and H3.2 are synthetized and loaded during DNA replication, the histone variant H3.3 is expressed and deposited into the chromatin throughout the cell cycle. Recent findings indicate that H3.3 replaces the majority of canonical H3 in non-dividing cells, reaching almost saturation levels in a time-dependent manner. Consequently, H3.3 incorporation and turnover represent an additional layer in the regulation of the chromatin landscape during aging. In this respect, work from our group and others suggest that H3.3 plays an important function in age-related processes throughout evolution. Here, we summarize the current knowledge on H3.3 biology and discuss the implications of its aberrant dynamics in the establishment of cellular states that may lead to human pathology. Critically, we review the importance of H3.3 turnover as part of epigenetic events that influence senescence and age-related processes. We conclude with the emerging evidence that H3.3 is required for proper neuronal function and brain plasticity.
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Affiliation(s)
- Daniele Bano
- German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
| | - Antonia Piazzesi
- German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
| | - Paolo Salomoni
- German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
| | - Pierluigi Nicotera
- German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
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Finnerty BM, Gray KD, Moore MD, Zarnegar R, Fahey III TJ. Epigenetics of gastroenteropancreatic neuroendocrine tumors: A clinicopathologic perspective. World J Gastrointest Oncol 2017; 9:341-353. [PMID: 28979716 PMCID: PMC5605334 DOI: 10.4251/wjgo.v9.i9.341] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 06/27/2017] [Accepted: 08/04/2017] [Indexed: 02/05/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEP-NET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA (lncRNA) differential expression profiles that are distinctive of GEP-NETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.
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Affiliation(s)
- Brendan M Finnerty
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Katherine D Gray
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Maureen D Moore
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Rasa Zarnegar
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Thomas J Fahey III
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
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Di Domenico A, Wiedmer T, Marinoni I, Perren A. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer 2017; 24:R315-R334. [PMID: 28710117 DOI: 10.1530/erc-17-0012] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 07/14/2017] [Indexed: 12/13/2022]
Abstract
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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Affiliation(s)
- Annunziata Di Domenico
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | - Tabea Wiedmer
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | | | - Aurel Perren
- Institute of PathologyUniversity of Bern, Bern, Switzerland
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Marinoni I, Wiederkeher A, Wiedmer T, Pantasis S, Di Domenico A, Frank R, Vassella E, Schmitt A, Perren A. Hypo-methylation mediates chromosomal instability in pancreatic NET. Endocr Relat Cancer 2017; 24:137-146. [PMID: 28115389 DOI: 10.1530/erc-16-0554] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 01/23/2017] [Indexed: 12/22/2022]
Abstract
DAXX and or ATRX loss occur in 40% of pancreatic neuroendocrine tumors (PanNETs). PanNETs negative for DAXX or ATRX show an increased risk of relapse. The tumor-associated pathways activated upon DAXX or ATRX loss and how this event may induce chromosomal instability (CIN) and alternative lengthening telomeres (ALT) are still unknown. Both DAXX and ATRX are involved in DNA methylation regulation. DNA methylation of heterochromatin and of non-coding sequences is extremely important for the maintenance of genomic stability. We analyzed the association of DAXX and/or ATRX loss and CIN with global DNA methylation in human PanNET samples and the effect of DAXX knock-down on methylation and cell proliferation. We assessed LINE1 as well as global DNA methylation in 167 PanNETs, and we found that DAXX and or ATRX-negative tumors and tumors with CIN were hypomethylated. DAXX knock-down in PanNET cell lines blocked cells in G1/G0 phase and seemed to increase CIN in QGP-1 cells. However, no direct changes in DNA methylation were observed after DAXX knock-down in vitro In conclusion, our data indicate that epigenetic changes are crucial steps in the progression of PanNETs loss and suggest that DNA methylation is the mechanism via which CIN is induced, allowing clonal expansion and selection.
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Affiliation(s)
- I Marinoni
- Institute of PathologyUniversity of Bern, Bern, Switzerland
| | - A Wiederkeher
- Institute of PathologyUniversity of Bern, Bern, Switzerland
| | - T Wiedmer
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- GCB Graduate School BernBern, Switzerland
| | - S Pantasis
- Institute of PathologyUniversity of Bern, Bern, Switzerland
| | - A Di Domenico
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- GCB Graduate School BernBern, Switzerland
| | - R Frank
- Institute of PathologyUniversity of Bern, Bern, Switzerland
| | - E Vassella
- Institute of PathologyUniversity of Bern, Bern, Switzerland
| | - A Schmitt
- Institute of PathologyUniversity of Bern, Bern, Switzerland
| | - A Perren
- Institute of PathologyUniversity of Bern, Bern, Switzerland
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Schmitt AM, Marinoni I, Blank A, Perren A. New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies. Endocr Pathol 2016; 27:200-4. [PMID: 27456058 DOI: 10.1007/s12022-016-9447-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.
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Affiliation(s)
- Anja M Schmitt
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3010, Bern, Switzerland.
| | - Ilaria Marinoni
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3010, Bern, Switzerland
| | - Annika Blank
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3010, Bern, Switzerland
| | - Aurel Perren
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3010, Bern, Switzerland
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Cives M, Simone V, Rizzo FM, Silvestris F. NETs: organ-related epigenetic derangements and potential clinical applications. Oncotarget 2016; 7:57414-57429. [PMID: 27418145 PMCID: PMC5302998 DOI: 10.18632/oncotarget.10598] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/30/2016] [Indexed: 12/15/2022] Open
Abstract
High-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications.
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Affiliation(s)
- Mauro Cives
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Valeria Simone
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Francesca Maria Rizzo
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
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Crona J, Skogseid B. GEP- NETS UPDATE: Genetics of neuroendocrine tumors. Eur J Endocrinol 2016; 174:R275-90. [PMID: 27165966 DOI: 10.1530/eje-15-0972] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 12/21/2015] [Indexed: 12/12/2022]
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.
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Affiliation(s)
- Joakim Crona
- Department of Medical SciencesUppsala University, Rudbecklaboratoriet, Dag hammarskjölds väg 20, 75185 Uppsala, Sweden
| | - Britt Skogseid
- Department of Medical SciencesUppsala University, Rudbecklaboratoriet, Dag hammarskjölds väg 20, 75185 Uppsala, Sweden
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Zatelli MC, Fanciulli G, Malandrino P, Ramundo V, Faggiano A, Colao A. Predictive factors of response to mTOR inhibitors in neuroendocrine tumours. Endocr Relat Cancer 2016; 23:R173-83. [PMID: 26666705 DOI: 10.1530/erc-15-0413] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 12/14/2015] [Indexed: 12/13/2022]
Abstract
Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.
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Affiliation(s)
- Maria Chiara Zatelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona - Ferrara, ItalyNeuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, ItalyEndocrinology UnitGaribaldi Nesima Medical Center, Catania, ItalyDepartment of Clinical Medicine and Surgery"Federico II" University of Naples, Naples, ItalyThyroid and Parathyroid Surgery UnitIstituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Giuseppe Fanciulli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona - Ferrara, ItalyNeuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, ItalyEndocrinology UnitGaribaldi Nesima Medical Center, Catania, ItalyDepartment of Clinical Medicine and Surgery"Federico II" University of Naples, Naples, ItalyThyroid and Parathyroid Surgery UnitIstituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Pasqualino Malandrino
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona - Ferrara, ItalyNeuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, ItalyEndocrinology UnitGaribaldi Nesima Medical Center, Catania, ItalyDepartment of Clinical Medicine and Surgery"Federico II" University of Naples, Naples, ItalyThyroid and Parathyroid Surgery UnitIstituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Valeria Ramundo
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona - Ferrara, ItalyNeuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, ItalyEndocrinology UnitGaribaldi Nesima Medical Center, Catania, ItalyDepartment of Clinical Medicine and Surgery"Federico II" University of Naples, Naples, ItalyThyroid and Parathyroid Surgery UnitIstituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Antongiulio Faggiano
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona - Ferrara, ItalyNeuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, ItalyEndocrinology UnitGaribaldi Nesima Medical Center, Catania, ItalyDepartment of Clinical Medicine and Surgery"Federico II" University of Naples, Naples, ItalyThyroid and Parathyroid Surgery UnitIstituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Annamaria Colao
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona - Ferrara, ItalyNeuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, ItalyEndocrinology UnitGaribaldi Nesima Medical Center, Catania, ItalyDepartment of Clinical Medicine and Surgery"Federico II" University of Naples, Naples, ItalyThyroid and Parathyroid Surgery UnitIstituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
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Minnetti M, Grossman A. Somatic and germline mutations in NETs: Implications for their diagnosis and management. Best Pract Res Clin Endocrinol Metab 2016; 30:115-27. [PMID: 26971848 DOI: 10.1016/j.beem.2015.09.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
It is now understood that specific somatic and germline mutations may lead to the development of the neuroendocrine tumours (NETs). NETs usually occur as sporadic isolated tumours, although they also may present as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), Von Hippel-Lindau (VHL) and neurofibromatosis syndromes, tuberous sclerosis, Carney triad and dyad, Reed syndrome and polycythaemia-paraganglioma syndromes. Only in MEN2 syndrome is there a specific genotype-phenotype correlation, although in both sporadic and syndromic NETs some gene mutations are associated with specific clinico-pathological features and prognosis. There have been several advances in our understanding of the NETs leading to earlier detection and targeted therapeutic treatment, but given the poor prognosis associated with metastatic NETs, it will be necessary to find new biomarkers for the prediction of malignant potential and to find novel therapeutic targets for NETs.
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Affiliation(s)
- Marianna Minnetti
- Dept. of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Dept. of Medicine, University of Oxford, UK
| | - Ashley Grossman
- Dept. of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Dept. of Medicine, University of Oxford, UK.
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How-Kit A, Dejeux E, Dousset B, Renault V, Baudry M, Terris B, Tost J. DNA methylation profiles distinguish different subtypes of gastroenteropancreatic neuroendocrine tumors. Epigenomics 2015; 7:1245-58. [PMID: 26360914 DOI: 10.2217/epi.15.85] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
AIM Most studies have considered gastroenteropancreatic neuroendocrine tumors (GEP-NETs) as a homogenous group of samples or distinguish only gastrointestinal from pancreatic endocrine tumors. This article investigates if DNA methylation patterns could distinguish subtypes of GEP-NETs. MATERIALS & METHODS The DNA methylation level of 807 cancer-related genes was investigated in insulinomas, gastrinomas, non-functioning pancreatic endocrine tumors and small intestine endocrine tumors. RESULTS DNA methylation patterns were found to be tumor type specific for each of the pancreatic tumor subtypes and identified two distinct methylation-based groups in small intestine endocrine tumors. Differences of DNA methylation levels were validated by pyrosequencing for 20 candidate genes and correlated with differences at the transcriptional level for four candidate genes. CONCLUSION The heterogeneity of DNA methylation patterns in the different subtypes of gastroenteropancreatic neuroendocrine tumors suggests different underlying pathways and, therefore, these tumors should be considered as distinct entities in molecular and clinical studies.
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Affiliation(s)
- Alexandre How-Kit
- Laboratory for Epigenetics & Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France.,Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France
| | - Emelyne Dejeux
- Laboratory for Epigenetics & Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France
| | - Bertrand Dousset
- Service de chirurgie digestive, hépatobiliaire et endocrinienne, Hôpital Cochin, AP-HP, Paris, France
| | - Victor Renault
- Laboratory for Bioinformatics, Fondation Jean Dausset - CEPH, Paris, France
| | - Marion Baudry
- Laboratory for Epigenetics & Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France.,Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France
| | - Benoit Terris
- Service d'Anatomie et de Cytologie Pathologique, Hôpital Cochin, AP-HP, Paris, France.,Institut Cochin de Génétique Moléculaire, Université Paris V René Descartes, CNRS (UMR8104), France.,Institut National de la Santé et de la Recherche Médicale U567, Paris, France
| | - Jörg Tost
- Laboratory for Epigenetics & Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France
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