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Anila Hashmi A Hashmi, Liverpool Hospital- Pathology Laboratory, NSW Health Pathology, Sydney, Australia

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Alexander Papachristos A Papachristos, Endocrine Surgery, Royal North Shore Hospital, St Leonards, Australia

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Stan B Sidhu S Sidhu, Department of Endocrine and Oncology Surgery, Royal North Shore Hospital, sydney, Australia

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Gyorgy Hutvagner G Hutvagner, School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia

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Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy characterised by diagnostic challenges, high recurrence rates, and poor prognosis. This study explored the role microRNA (miRNA) processing genes in ACC, and their potential role as diagnostic and prognostic biomarkers. We analysed the mRNA expression levels of miRNA machinery components (DROSHA, DGCR8, XPO5, RAN, DICER, TARBP2 and AGO2) utilising mRNA-Seq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) projects. Additionally, protein levels were quantified in tissue samples from the Kolling Institute of Medical Research's tumour bank. Our results demonstrated that among all miRNA processing components, AGO2 exhibited significant overexpression in ACC compared to the normal adrenal cortex (NAC) and benign adrenal adenoma (AA) (p < 0.001). Kaplan–Meier survival analysis indicated that higher AGO2 expression correlated with significantly worse overall survival in ACC patients (HR 7.07, p < 0.001). Among 32 cancer types in TCGA, the prognostic significance of AGO2 was most prominent in ACC. This study is the first to report AGO2's potential as a diagnostic and prognostic biomarker in ACC, emphasising its significance in ACC pathogenesis and potential application as a non-invasive liquid biopsy biomarker.

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Timothy J. Walker T Walker, Pathology & Molecular Medicine, Queen's University, Kingston, Canada

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Lois M Mulligan L Mulligan, Pathology & Molecular Medicine, Queen's University, Kingston, Canada

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REarranged during Transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point-mutations give rise to the inherited cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of ligand. These mutations cause intrinsic biochemical changes in RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Together, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to differences in tumour progression and disease aggressiveness.

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Maaia Margo Jentus M Jentus, Department of Pathology, Leiden University Medical Center, Leiden, Netherlands

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Leontine Bakker L Bakker, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Marco Verstegen M Verstegen, Department of Neurosurgery, Leiden University Medical Center, Leiden, Netherlands

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Iris Pelsma I Pelsma, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Tom van Wezel T van Wezel, Pathology, Leiden University Medical Center, Leiden, Netherlands

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Dina Ruano D Ruano, Pathology, Leiden University Medical Center, Leiden, Netherlands

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Ellen Kapiteijn E Kapiteijn, Medical Oncology, Leiden University Medical Center, Leiden, Netherlands

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Stijn Crobach S Crobach, Department of Pathology, Leiden University Medical Center, Leiden, Netherlands

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Nienke R. Biermasz N Biermasz, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands

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Hans Morreau H Morreau, Pathology, Leiden University Medical Center, Leiden, Netherlands

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The molecular biology of pituitary neuroendocrine tumors (PitNETs) revealed few recurrent mutations and extensive chromosomal alterations, with the latter being the driving force in a subset of these lesions. Addressing the need for an easily applicable diagnostic tool, we conducted a retrospective study of 61 PitNETs operated at a tertiary care center. All cases were subtyped according to the 2022 WHO classification of endocrine tumors. A genome wide NGS panel targeting 1500 single-nucleotide polymorphisms (SNP) was used to classify chromosomal imbalances, loss of heterozygosity and copy number variations in DNA from formalin fixed paraffin embedded tissues. We identified four distinct chromosomal patterns, with varying distribution among different tumor lineages. Forty-two of 61 (69%) PitNETs showed chromosomal alterations. Gonadotroph PitNETs showed mostly quiet genomes. The majority of lactotroph PitNETs (19/20, 95%) were altered, exhibiting a gained genome and a remarkably low recurrence rate. Nine of ten (90%) corticotroph PitNETs harbored chromosomal alterations, of which two aggressive corticotroph tumors and one metastatic corticotroph PitNET showed massive chromosomal losses leading to near haploid/near homozygous genomes. The comparison of the molecular profile of primary and recurrent PitNETs of five patients showed no significant accumulation of alterations over time. A simple genome wide 1500 SNP test can be used in the identification of outspoken aggressive subsets of PitNET by the occurrence of a near haploid/near homozygous genome. Furthermore, the presence of neoplastic tissue in resected material can be potentially confirmed for non-gonadotroph PitNETs in suboptimal histological assessment conditions.

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Frederic Castinetti F Castinetti, Endocrinology, INSERM, Paris, France

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Charis Eng C Eng, Genomic Medicine Institute, Cleveland Clinic, Cleveland, United States

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Multiple endocrine neoplasia type 2 (MEN 2) is a rare hereditary endocrine tumour syndrome caused by mutations in the rearranged during transfection (RET) gene. MEN 2 is divided into two main entities, MEN 2A and MEN2B, both of which present with medullary thyroid cancer (MTC) in approximately 100% of cases and pheochromocytoma in 50% of cases. Specific RET mutations are associated with a risk of early onset of MTC, from 1 year of age (highest risk) to 5 years of age (high risk). This risk defines the optimal timing for thyroidectomy, ideally at an age when the disease has not spread. This is the most important genotype-phenotype correlation observed in MEN 2. Specific RET mutations also define the penetrance of pheochromocytoma. However, despite the presence of these highest/high risk variants, some patients unexpectedly present with non-aggressive MTC or never present with pheochromocytoma, suggesting that factors other than the major RET variant may modify the natural history and genotype-phenotype correlations. Improving our understanding of the genotype-phenotype correlations would allow individualizing the management and follow-up of patients with MEN 2. The aim of this brief review is to discuss the main genotype-phenotype correlations in MEN 2 and the potential factors that might influence these correlations.

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Deborah J Marsh D Marsh, School of Life Sciences, Kolling Institute of Medical Research, Ultimo, 2007, Australia

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Lois M Mulligan L Mulligan, Pathology and Molecular Medicine, Queen's University, Kingston, Canada

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Joanne Ngeow J Ngeow, National Cancer Centre Singapore, National cancer Centre , singapore, Singapore

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Matthew D Ringel M Ringel, Medicine, The Ohio State University, Columbus, 43210, United States

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Constantine A Stratakis C Stratakis, NICHD, NIH, Bethesda, MD 20892, United States

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Matthew Ringel On behalf of the entire editorial team of Endocrine-Related Cancer, and personally as trainees and collaborators who at present serve as associate or senior editors of the Journal, it is with profound sadness that we write this memorial to Prof. Charis Eng, M.D., Ph.D who passed away on August 13, 2024. Prof. Eng served as Editor-in-Chief of Endocrine-Related Cancer from 2011-2021 and was dedicated to the Journal before, during, and after she served in that role. She had remarkable impact on Endocrine-Related Cancer moving the journal forward with great vision and energy while maintaining the strongest commitments to publishing the highest quality original research and reviews applying fair, ethical, and rigorous peer-review processes. Charis was a world-recognized leader in cancer genomics and clinical genetics medicine who enabled growth in Endocrine-Related Cancer in these and other areas critical for advancement of research and clinical care of endocrine cancers. She will be remembered by all of us as a superb and consequential researcher, editor, physician, leader, teacher, mentor, colleague, and friend.

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Caroline Brain C Brain, Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom of Great Britain and Northern Ireland

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Joanna Grey J Grey, CEO, Association for Multiple Endocrine Neoplasia Disorders, Tonbridge, United Kingdom of Great Britain and Northern Ireland

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Kirstie Purnell K Purnell, Volunteer, Association for Multiple Endocrine Neoplasia Disorders, Leicester, United Kingdom of Great Britain and Northern Ireland

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Multiple endocrine neoplasia type 2 (MEN2) is the collective term for 2 distinct types of autosomal dominantly inherited neuroendocrine neoplasm (NEN) syndromes (Barakat, 2004); MEN2A and MEN 2B (or MEN3). MEN2 is characterised by medullary thyroid cancer (99%) and phaeochromocytoma (50%) but also other conditions according to specific genotype. MEN2A also includes a 25% risk of developing parathyroid hyperplasia and is now recognised as 4 separate syndromes: Classic MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung’s disease (HD) and Familial MTC (Wells, 2015). MEN2B accounts for around 5% of all MEN2 cases and predisposes patients to diffuse intestinal ganglioneuromatosis (Goncharova, 2020), mucosal neuromas, and musculoskeletal abnormalities (Henderson, 2022). MEN2 is autosomal dominantly inherited meaning that several generations in a single family may be affected by the same syndrome. We present a mini review of 4 case studies (x2 MEN2A, x2 MEN2B) that illustrate the advantages of RET testing, as well as some of the likely obstacles that must be overcome to receive a diagnosis of MEN2A or MEN2B. In addition, despite improved genotype/phenotype correlation in MEN2, we highlight that not all cases are ‘typical’ which emphasises the need for all MEN2 patients to be cared for in a centre of expertise and experience. Some of our case study patients or parents also took this opportunity to personally tell us more about their lives with MEN2, illustrating the need for more research into the psychosocial impact of these hereditary diseases.

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A Mohamed Division of Hematology and Medical Oncology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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M Trybula Division of Hematology and Medical Oncology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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S L Asa Department of Medicine, UH Seidman Cancer Center Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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T R Halfdanarson Division of Medical Oncology, Department of Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota, USA

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M B Sonbol Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Phoenix, Arizona, USA

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The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NENs are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in the grading system changed the definition of grade 3 to include high-grade well-differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis, and clinical behavior, which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited, which impacts their management. In this review, we will summarize the current advances in the multidisciplinary approach for the management of high-grade gastroenteropancreatic NENs (GEP-NENs) including G3-NETs and NECs.

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Francesca Carlomagno F Carlomagno, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy

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Marialuisa Moccia M Moccia, Istituto di Endocrinologia e Oncologia Sperimentale , Consiglio Nazionale delle Ricerche, Napoli, Italy

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Giorgia Federico G Federico, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy

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Massimo Santoro M Santoro, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy

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The RET receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor (GDNF) family (GFLs) and by the growth differentiation factor-15 (GDF15) cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.

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Andrew McDonald Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Vaidehi Avadhani Grady Memorial Hospital, Atlanta, Georgia, USA

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Gabriela Oprea-Ilies Grady Memorial Hospital, Atlanta, Georgia, USA

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Katerina Zakka Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Gregory B Lesinski Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Olumide B Gbolahan Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Olatunji Alese Winship Cancer Institute at Emory University, Atlanta, Georgia, USA

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Gastroenteropancreatic high-grade (HG) neuroendocrine carcinoma (GEP-NEC) is an aggressive malignancy with limited treatment options and increasing incidence in the United States. Due to the rarity of the cancer and heterogeneity of the primary tumor location, data on GEP-NEC oncogenesis and its interaction with the host immune system are limited. A greater understanding of GEP-NEC and its tumor microenvironment (TME) would benefit efforts to develop more effective targeted therapies and rationally adapt immunotherapy to this disease. In this study, we profiled the expression of 770 unique genes using 21 biopsy samples from patients with GEP-NEC using the NanoString nCounter PanCancer IO 360 platform. Our results show several trends evident within the GEP-NEC TME. Greater expression of genes indicative of immune cell infiltration was present within the TME of patients <60 years of age and in patients with greater overall survival (OS). Tumors from patients with non-pancreatic NEC had diminished MHCII expression compared to pancreatic NEC, suggesting more prominent adaptive immune responses in the pancreatic GEP-NEC subtype. Patients with a >6 months OS had tumors with elevated NK cell gene signatures compared to patients with poor survival. Further, the analysis revealed numerous differentially expressed genes based on patient age, tumor location, response to treatment, and OS, which warrant future validation for assessing the relationship with clinical outcomes in patients.

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William Reed Doerfler W Doerfler, Department of Medicine, University of Pittsburgh, Pittsburgh, United States

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Alyaksandr V. Nikitski A Nikitski, Department of Pathology , University of Pittsburgh, Pittsburgh, United States

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Shannon Keating S Keating, Department of Pathology, University of Pittsburgh, Pittsburgh, United States

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Daniel Spagnolo D Spagnolo, Department of Pathology, University of Pittsburgh, Pittsburgh, United States

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Cihan Kaya C Kaya, Department of Pathology, University of Pittsburgh, Pittsburgh, United States

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Elena Morariu E Morariu, Department of Medicine, University of Pittsburgh, Pittsburgh, 15261, United States

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Esra Karslioglu French E Karslioglu French, Department of Medicine, University of Pittsburgh, Pittsburgh, 15261, United States

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Linwah Yip L Yip, Department of Surgery, University of Pittsburgh, Pittsburgh, United States

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Marina N Nikiforova M Nikiforova, Department of Pathology, University of Pittsburgh, Pittsburgh, United States

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Abigail I Wald A Wald, Department of Pathology, University of Pittsburgh, Pittsburgh, United States

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Yuri E Nikiforov Y Nikiforov, Department of Pathology, University of Pittsburgh, Pittsburgh, United States

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BRAFK601E is an uncommon mutation typically found in encapsulated follicular-patterned thyroid tumors. Previous studies on BRAFK601E-positive thyroid tumors were conducted before implementation of the non-invasive follicular neoplasm with papillary-like nuclear features (NIFTP) diagnosis. This study aimed to characterize BRAFK601E-positive tumors and evaluate changes in diagnosis and management of these patients after introduction of NIFTP. We evaluated 25 thyroid tumors that were positive for BRAFK601E and diagnosed considering the NIFTP criteria. Clinicopathologic characteristics and recurrence rates of these tumors were compared to 29 BRAFK601E-positive tumors diagnosed prior to the acceptance of NIFTP diagnosis. RNA-seq analysis was performed on 10 BRAFK601E-positive tumors. In the current study, 72% of BRAFK601E-positive tumors were diagnosed as non-invasive tumors on resection, with NIFTP (48% of all tumors) being the most common diagnosis. BRAFK601E-positive tumors exhibited a RAS-like gene expression profile with BRAF-RAS score (BRS) and thyroid differentiation score (TDS) distinct from BRAFV600E-positive tumors (P<0.001). Since 2016, patients with BRAFK601E-positive tumors less frequently underwent total thyroidectomy (41% vs 100%, P<0.001) and received radioiodine (7% vs 75%, P<0.001). None of the tumors positive for an isolated BRAFK601E mutation from the current or 2016 studies showed recurrences on follow-up. Our study demonstrates that most BRAFK601E-positive tumors are low risk, RAS-like tumors, which were diagnosed as NIFTP in half of all study cases. Since 2016, patients with BRAFK601E-positive nodules receive less aggressive treatment. The risk of recurrence of BRAFK601E-positive tumors without other, high-risk features appears to be low, and lobectomy without radioiodine is likely sufficient treatment for these patients.

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