Molecular Profiling for Proper Diagnosis of Gastroenteropancreatic Neuroendocrine Tumor.
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ABSTRACT:
SUBMITTER: Serei VD
PROVIDER: S-EPMC7446509 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are a relatively rare, heterogeneous group of diseases in which important advances have been observed in the diagnosis and treatment as well as in our understanding of the biology and genetics of the disease in recent years. Given the insufficient scientific data available on evidence-based management of GEPNETs and the differences in circumstances in individual countries, a multidisciplinary study group was established to provide guidelines for the management of GEPNETS. This study group consisted of a medical oncologist, endocrinologist, surgeon, pathologist, gastroenterologist, and a nuclear medicine specialist, who aimed to prepare a practical guide in the light of existing scientific data and international guidelines, to be used in common clinical practice.
| S-EPMC5332464 | biostudies-other
Project description:Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) arise from neuroendocrine cells found throughout the gastrointestinal tract and islet cells of the pancreas. The incidence and prevalence of GEP-NENs have been increasing each year due to higher awareness, improved diagnostic modalities, and increased incidental detection on cross-sectional imaging and endoscopy for cancer screening and other conditions and symptoms. GEP-NENs are a heterogeneous group of tumors and have a wide range in clinical presentation, histopathologic features, and molecular biology. Clinical presentation most commonly depends on whether the GEP-NEN secretes an active hormone. The World Health Organization recently updated the classification of GEP-NENs to introduce a distinction between high-grade neuroendocrine tumors and neuroendocrine carcinomas, which can be identified using histology and molecular studies and are more aggressive with a worse prognosis compared to high-grade neuroendocrine tumors. As our understanding of the biology of GEP-NENs has grown, new and improved diagnostic modalities can be developed and optimized. Here, we discuss clinical features and updates in diagnosis, including histopathological analysis, biomarkers, molecular techniques, and radiology of GEP-NENs. We review established diagnostic tests and discuss promising novel diagnostic tests that are currently in development or require further investigation and validation prior to broad utilization in patient care.
| S-EPMC8968521 | biostudies-literature
Project description:We have conducted molecular profiling through a high-throughput molecular test as part of our clinical practice for patients with advanced gastrointestinal (GI) cancer or rare cancers including gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Herein, we report on the molecular characterization of 14 metastatic GEP-NET patients.We conducted the Ion AmpliSeq Cancer Hotspot Panel v2 (detecting 2,855 oncogenic mutations in 50 commonly mutated genes) and nCounter Copy Number Variation Assay, which was designed with 21 genes based on available targeted agents, as a high throughput genomic platform in 14 patients with metastatic GEP-NETs.Among the 14 GEP-NET patients analyzed in this study, 8 patients had grade III neuroendocrine carcinoma (NEC) and 6 had grade I/II NET. Primary sites included pancreas (n=3), small intestine and ascending colon (n=3), distal colon and rectum (n=5), and unknown primary origin (n=3). The most common metastatic site was the liver. Of 14 GEP-NET patients available for mutational profiling, 7 (50.0%) patients had one or more aberrations detected. Common aberrations were as follows: SMARCB1 mutation (n=2), TP53 mutation (n=2), STK11 mutation (n=1), RET mutation (n=1), and BRAF mutation (n=1). Gene amplification by nCounter was detected in only 1 patient, showing CCNE1 amplification, and this patient also had a TP53 mutation.This high throughput genomic test may be useful to identify new drug targets in metastatic GEP-NET patients. Currently, we plan to conduct further genomic analysis to develop predictive and prognostic biomarkers in a larger number of GEP-NET patients.
| S-EPMC4911870 | biostudies-literature
Project description:PurposeGEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between gastrointestinal (GI) and pancreatic (PNEN), high-grade (HG), and low-grade (LG) tumors.Experimental designGEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and in situ hybridization. Tumor mutational burden (TMB) was calculated on the basis of somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci.ResultsIn total, 724 GEP-NENs were examined: GI (N = 469), PNEN (N = 255), HG (N = 135), and LG (N = 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were ATRX (13%), ARID1A (10%), and MEN1 (10%). HG tumors showed TP53 (51%), KRAS (30%), APC (27%), and ARID1A (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG [MSI-H 0% vs. 4% (P = 0.04), PD-L1 overexpression 1% vs. 6% (P = 0.03), TMB-high 1% vs. 7% (P = 0.05)]. Compared with LG, HG NENs showed a higher mutation rate in BRAF (5.4% vs. 0%, P < 0.0001), KRAS (29.4% vs. 2.6%, P < 0.0001), and PI3KCA (7% vs. 0.3%, P < 0.0001). When compared with GI, PNEN carried higher frequency of MEN1 (25.9% vs. 0.0%, P < 0.0001), FOXO3 (8.6% vs. 0.8%, P = 0.005), ATRX (20.6% vs. 2.0%, P = 0.007), and TSC2 (6.3% vs. 0.0%, P = 0.007), but lower frequency of mutations in APC (1.0% vs. 13.8%, P < 0.0001).ConclusionsSignificant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.
| S-EPMC8970533 | biostudies-literature
Project description:The molecular events leading to gastroenteropancreatic neuroendocrine tumor (GEP-NET) formation are largely unknown. Over the past decades, systemic chemotherapies have been replaced by therapies directed at particular molecular targets such as the somatostatin receptors, mTOR complexes or proangiogenic molecules. These approaches have demonstrated some success in subtypes of this heterogeneous tumor group, but responses are still widely varied. This review highlights the clinical trials ongoing for neuroendocrine tumors (NETs) and includes emerging immunotherapy, which holds great promise for NETs based on successes in other tumor types. Current avenues of preclinical research, including Notch and PI3K/AKT, will lead to additional targeted therapies based on genome-wide studies that have cast a wide net in the search for driver mutations. Future preclinical and clinical investigations are required to identify those mutations predictive of therapeutic response or disease progression. Results of current clinical trials outlined here will better inform patient management with respect to agent selection, timing, duration and combination therapy in the treatment of NETs.
| S-EPMC5722794 | biostudies-literature
Project description:High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.
| S-EPMC8630776 | biostudies-literature
Project description:Neuroendocrine neoplasms (NENs) are an increasingly common cause of neoplastic diseases. One of the largest groups of NENs are neoplasms localized to the gastroenteropancreatic system, which are known as gastroenteropancreatic NENs (GEP-NENs). Because of nonspecific clinical symptoms, GEP-NEN patient diagnosis and, consequently, their treatment, might be difficult and delayed. This situation has forced researchers all over the world to continue progress in the diagnosis and treatment of patients with GEP-NENs. Our review is designed to present the latest reports on the laboratory diagnostic techniques, imaging tests and surgical and nonsurgical treatment strategies used for patients with these rare neoplasms. We paid particular attention to the nuclear approach, the use of which has been applied to GEP-NEN patient diagnosis, and to nonsurgical and radionuclide treatment strategies. Recent publications were reviewed in search of reports on new strategies for effective disease management. Attention was also paid to those studies still in progress, but with successful results. A total of 248 papers were analyzed, from which 141 papers most relevant to the aim of the study were selected. Using these papers, we highlight the progress in the development of diagnostic and treatment strategies for patients with GEP-NENs.
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Project description:Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), considered a heterogeneous neoplasia, exhibit ill-defined pathobiology and protean symptomatology and are ubiquitous in location. They are difficult to diagnose, challenging to manage, and outcome depends on cell type, secretory product, histopathologic grading, and organ of origin. A morphologic and molecular genomic review of these lesions highlights tumor characteristics that can be used clinically, such as somatostatin-receptor expression, and confirms features that set them outside the standard neoplasia paradigm. Their unique pathobiology is useful for developing diagnostics using somatostatin-receptor targeted imaging or uptake of radiolabeled amino acids specific to secretory products or metabolism. Therapy has evolved via targeting of protein kinase B signaling or somatostatin receptors with drugs or isotopes (peptide-receptor radiotherapy). With DNA sequencing, rarely identified activating mutations confirm that tumor suppressor genes are relevant. Genomic approaches focusing on cancer-associated genes and signaling pathways likely will remain uninformative. Their uniquely dissimilar molecular profiles mean individual tumors are unlikely to be easily or uniformly targeted by therapeutics currently linked to standard cancer genetic paradigms. The prevalence of menin mutations in pancreatic NEN and P27KIP1 mutations in small intestinal NEN represents initial steps to identifying a regulatory commonality in GEP-NEN. Transcriptional profiling and network-based analyses may define the cellular toolkit. Multianalyte diagnostic tools facilitate more accurate molecular pathologic delineations of NEN for assessing prognosis and identifying strategies for individualized patient treatment. GEP-NEN remain unique, poorly understood entities, and insight into their pathobiology and molecular mechanisms of growth and metastasis will help identify the diagnostic and therapeutic weaknesses of this neoplasia.
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Project description:Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogenous group of malignancies originating from neuroendocrine cells of the gastrointestinal tract, the incidence of which has been increasing for several decades. While there has been significant progress in the development of therapeutic options for patients with advanced or metastatic disease, these remain limited both in quantity and durability of benefit. This review examines the latest research elucidating the mechanisms of both up-front resistance and the eventual development of resistance to the primary systemic therapeutic options including somatostatin analogues, peptide receptor radionuclide therapy with lutetium Lu 177 dotatate, everolimus, sunitinib, and temozolomide-based chemotherapy. Further, potential strategies for overcoming these mechanisms of resistance are reviewed in addition to a comprehensive review of ongoing and planned clinical trials addressing this important challenge.
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Project description:Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.
| S-EPMC9221445 | biostudies-literature