Comprehensive study of genetic features of pancreatic neuroendocrine tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16699-e16699
Author(s):  
Vladimir S. Trifanov ◽  
Oleg I. Kit ◽  
Dmitry Yu. Gvaldin ◽  
Natalya N. Timoshkina ◽  
Sergey V. Sanamyants ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Neuroendocrine Tumors ◽  
Molecular Genetic ◽  
Genetic Alterations ◽  
Pancreatic Neuroendocrine Tumors ◽  
Loss Of Function ◽  
Rare Type ◽  
Genetic Changes ◽  
Genetic Features ◽  
American Society

e16699 Background: Pancreatic neuroendocrine tumors (panNETs) are a heterogeneous, relatively rare type of neoplasm which distinguishes a long clinical course in a large number of cases, that leads to the fact that the prevalence rate of NETs is one of the highest. The purpose of this study was a research the mutational profiles of panNETs of various grades of malignancy and to search for new candidate genes involved in the oncogenic processes of this pathology. Methods: The study included a retrospective group of 24 patients (10 men, 14 women, median age - 60 years old) with a diagnosis of panNET, treated in the RRIO from 2011 to 2018. Comprehensive cancer panel (409 genes) were used for NGS procedure on the NextSeq 550 platform(Illumina, USA). To work with raw data, we used the standard pipeline proposed by BaseSpace (Illumina, USA). Interpretation of the identified variants was carried out in accordance with the recommendations of the Association for Molecular Pathology, American Society of Clinical Oncology and College of American Pathologists. Results: 119 mutations in 54 genes were detected in samples of panNETs. 26 genetic variations were characterized as new, not previously described for panNETs. 18% of the mutations were activating, 35% of the variants led to a loss of function of the encoded protein, 52% were not classified. Candidate genes that have not been previously described in the literature and which are potentially involved in pancreatic oncogenesis are identified: CREB1, TCF12, PRKAR1A, BCL11A and BUB1B. The largest number of mutational events occurred in the genes responsible for histone methylation; in addition, 38% described genetic alterations in the regulation of the SMAD2/3 signaling pathway. Conclusions: According to the NGS study of panNETs of low and moderate malignancy in the Russian cohort, a unique spectrum of 119 mutations was obtained, of which 26 were not previously described. The discovered molecular genetic changes in the signaling pathways underline the importance of impaired epigenetic control of transcription in pancreatic oncogenesis and open up new prospects for targeted therapy.

Molecular-Genetic Features of Pancreatic Neuroendocrine Tumors

2020 ◽  
Vol 56 (2) ◽  
pp. 142-158
Author(s):  
O. I. Kit ◽  
D. Yu. Gvaldin ◽  
V. S. Trifanov ◽  
E. N. Kolesnikov ◽  
N. N. Timoshkina
Keyword(s):  
Neuroendocrine Tumors ◽  
Molecular Genetic ◽  
Pancreatic Neuroendocrine Tumors ◽  
Genetic Features

Comprehensive Genetic and Histopathologic Study Reveals Three Types of Neuroblastoma Tumors

2001 ◽  
Vol 19 (12) ◽  
pp. 3080-3090 ◽  
Author(s):  
Maria Łastowska ◽  
Catherine Cullinane ◽  
Sadick Variend ◽  
Simon Cotterill ◽  
Nick Bown ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Genetic Alterations ◽  
Good Prognosis ◽  
Mycn Amplification ◽  
Genetic Changes ◽  
Pathology Classification ◽  
Genetic Features ◽  
1P Deletion ◽  
Tumor Types ◽  
Type 3

PURPOSE: To determine the relationship between multiple genetic features, tumor morphology, and prognosis in neuroblastoma. PATIENTS AND METHODS: The genetic alterations and morphologic features that underpin three histopathologic risk classifications were analyzed in 108 neuroblastoma patients. Tumors were subdivided into four groups based on the three most frequent and prognostically significant genetic alterations (17q gain, 1p deletion, and MYCN amplification), and all other genetic, morphologic, and clinical data were analyzed with respect to these groups. RESULTS: Our analyses identify three nonoverlapping tumor types with distinct genetic and morphologic features, defined here as types 1, 2, and 3. Type 1 tumors show none of the three significant genetic alterations and have good prognosis. Both type 2 (17q gain only or 17q gain and 1p del) and type 3 (17q gain, 1p del, and MYCN amplification) tumors progress. However, these tumor types are distinguished clinically by having significantly different median age at diagnosis and median progression-free survival (PFS). Multivariate analysis indicates that 17q gain is the only independent prognostic factor among all genetic, histopathologic, and clinical factors analyzed. Among histopathologic risk systems, the International Neuroblastoma Pathology Classification was the best predictor of PFS. CONCLUSION: Our results indicate that specific combinations of genetic changes in neuroblastoma tumors contribute to distinct morphologic and clinical features. Furthermore, the identification of two genetically and morphologically distinct types of progressing tumors suggests that possibilities for different therapeutic regimens should be investigated.

Using Zebrafish to Test the Genetic Basis of Human Craniofacial Diseases

2017 ◽  
Vol 96 (11) ◽  
pp. 1192-1199 ◽  
Author(s):  
R. Grecco Machado ◽  
B. Frank Eames
Keyword(s):  
Candidate Genes ◽  
Genetic Manipulation ◽  
Association Studies ◽  
Underlying Disease ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Loci ◽  
Large Numbers ◽  
Genetic Features ◽  
New Treatments

Genome-wide association studies (GWASs) opened an innovative and productive avenue to investigate the molecular basis of human craniofacial disease. However, GWASs identify candidate genes only; they do not prove that any particular one is the functional villain underlying disease or just an unlucky genomic bystander. Genetic manipulation of animal models is the best approach to reveal which genetic loci identified from human GWASs are functionally related to specific diseases. The purpose of this review is to discuss the potential of zebrafish to resolve which candidate genetic loci are mechanistic drivers of craniofacial diseases. Many anatomic, embryonic, and genetic features of craniofacial development are conserved among zebrafish and mammals, making zebrafish a good model of craniofacial diseases. Also, the ability to manipulate gene function in zebrafish was greatly expanded over the past 20 y, enabling systems such as Gateway Tol2 and CRISPR-Cas9 to test gain- and loss-of-function alleles identified from human GWASs in coding and noncoding regions of DNA. With the optimization of genetic editing methods, large numbers of candidate genes can be efficiently interrogated. Finding the functional villains that underlie diseases will permit new treatments and prevention strategies and will increase understanding of how gene pathways operate during normal development.

scholarly journals Update on the Surgical Treatment of Pancreatic Neuroendocrine Tumors

2020 ◽  
Vol 109 (1) ◽  
pp. 42-52 ◽  
Author(s):  
F. Jeune ◽  
A. Taibi ◽  
S. Gaujoux
Keyword(s):  
Surgical Management ◽  
Neuroendocrine Tumors ◽  
English Language ◽  
Hormone Secretion ◽  
Genetic Alterations ◽  
Tumor Board ◽  
Pancreatic Neuroendocrine Tumors ◽  
Genetic Syndromes ◽  
Cross Sectional ◽  
Management Alternative

Background and Aims: Pancreatic neuroendocrine tumors (PNET) arise from uncontrolled proliferation of neuroendocrine cell and further genetic alterations that may induce hormone secretion such as glucagon/insulin/gastrin/VIP. Their incidence is rapidelly growing, especially because of the frequent incidental diagnosis of small asymptomatic non-functionnal neuroendocrine tumors with the widespread use of cross-sectional imaging. The vast majority of pancreatic neuroendocrine tumors are sporadic but up to 5%–10% of them arise from genetic syndromes, the main one being Multiple Endocrine Neopalsm type 1 (MEN1). Appropriate management of patients with PNET is a complex challenge for surgeons, and require extensive medical collaboration. This review aims to summarize major and recent updates regarding the medico-surgical management of PNETs. Material and Methods: Review of pertinent English language literature. Results: This article provides a concise summary of the clinical presentation, diagnosis, surgical management, alternative treatments and follow up of PNETs. Conclusion: PNET are a rare, heterogeneous group of neoplasms with a generally favorable prognosis at least compared to pancreatic adenocarcinoma. Surgical resection is the cornerstone of their management, particularly for localized disease, and should always be discussed in multidisciplinary tumor board.

scholarly journals Modern aspects of morphology of endometrial cancer and neuroendocrine tumors (to the 100th anniversary of the birth of O.K. Khmelnitsky)

2021 ◽  
Vol 102 (4) ◽  
pp. 581-586
Author(s):  
E M Nepomnyashchaya ◽  
T I Moiseenko ◽  
V S Trifanov
Keyword(s):  
Endometrial Cancer ◽  
Neuroendocrine Tumors ◽  
Molecular Genetic ◽  
Genetic Research ◽  
Morphological Characteristics ◽  
100Th Anniversary ◽  
Medical Sciences ◽  
Genetic Classification ◽  
Genetic Changes

November 4, 2020, marks the 100th anniversary of the birth of Oleg Konstantinovich Khmelnitskiy, an outstanding Russian pathologist, Corresponding Member of the Russian Academy of Medical Sciences (04.11.192008.02.2004). The creative legacy of O.K. Khmelnitskiy has a large number of works devoted to endometrial cancer and neuroendocrine tumors. Modern concepts of these tumors take a lot from the scientists ideas. The development of the classification of endometrioid carcinomas is determined by new data in molecular genetic research. The most common genetic changes in endometrioid adenocarcinomas involve mutations in the PTEN, KRAS, CTNNB1, PIK3CA, and MS1 genes. Serous carcinomas are characterized by TP53 mutations and HER2-neu gene amplification. The immunohistochemical panel allows differentiation of endometrioid and serous carcinomas. There is evidence of the role of the POLE gene mutation. Various advantages of the introduction of molecular genetic classification are presented, which allow changing approaches to the treatment of endometrial cancer depending on the risk of its development. The 2019 neuroendocrine tumors (NETs) classification allows interpreting morphological characteristics of these tumors in a new way.

scholarly journals Molecular Signatures and Their Clinical Utility in Pancreatic Neuroendocrine Tumors

2021 ◽  
Vol 11 ◽  
Author(s):  
Praveen Dilip Chatani ◽  
Sunita Kishore Agarwal ◽  
Samira Mercedes Sadowski
Keyword(s):  
Next Generation Sequencing ◽  
Neuroendocrine Tumors ◽  
Clinical Utility ◽  
Genetic Alterations ◽  
Pharmaceutical Products ◽  
Molecular Signatures ◽  
Pancreatic Neuroendocrine Tumors ◽  
Histologic Differentiation ◽  
Proliferative Indices ◽  
Generation Sequencing

Pancreatic neuroendocrine tumors (PNETs) are classified based on their histologic differentiation and proliferative indices, which have been used extensively to determine prognosis. Advances in next-generation sequencing and other high-throughput techniques have allowed researchers to objectively explore tumor specimens and learn about the genetic alterations associated with malignant transformation in PNETs. As a result, targeted, pathway-specific therapies have been emerging for the treatment of unresectable and metastatic disease. As we continue to trial various pharmaceutical products, evidence from studies using multi-omics approaches indicates that clinical aggressiveness stratifies along other genotypic and phenotypic demarcations, as well. In this review, we explore the clinically relevant and potentially targetable molecular signatures of PNETs, their associated trials, and the overall differences in reported prognoses and responses to existing therapies.

Widespread somatic loss of heterozygosity as a possible marker of disease aggressiveness in metastatic well differentiated pancreatic neuroendocrine tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 275-275
Author(s):  
Omobolaji Oyekunle Akala ◽  
Ronak Shah ◽  
Brian R. Untch ◽  
Virginia Kelly ◽  
Joanne F. Chou ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Neuroendocrine Tumors ◽  
Copy Number ◽  
Tumor Biology ◽  
Genetic Alterations ◽  
Routine Practice ◽  
Tumor Type ◽  
Pancreatic Neuroendocrine Tumors ◽  
Pathologic Features ◽  
Well Differentiated

275 Background: To assess the utility of molecular profiling to predict tumor biology, we performed next-generation sequencing (NGS) of metastatic well differentiated (WD) pancreatic neuroendocrine tumors (panNETs) in the routine practice setting. Our institutional NGS platform allows for evaluation of genetic alterations that contribute to tumorigenesis (sequence variants, copy number alterations, insertions/deletions, select rearrangements) as well as somatic loss of heterozygosity (LOH). Methods: NGS was performed using MSK-IMPACT, a matched tumor-normal sequencing platform that interrogates 468 cancer-related genes. LOH for all cases was determined by analysis of total, allele-specific, and integer DNA copy number genome-wide using the FACETS algorithm. Results: Since 2014, NGS has been performed in 96 tumor samples from 80 patients. The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). LOH was highly prevalent, identified in 51/96 samples (53%). A significant association (q-value < 0.05) was noted between LOH and the presence of altered MEN1, DAXX, PTEN, or TSC2. LOH was recurrently observed in chromosomes 1, 2, 3, 6, 8, 10, 11, 15, 16, 21, and 22. Since MEN1 alterations predict improved outcome, comparison was made between patients with LOH present/MEN1 wild type (WT) tumors (n = 16) and LOH absent/MEN1 altered tumors (n = 21); inferior overall survival (OS) was noted with LOH present/MEN1 WT status (p < 0.01). High grade pathology was observed in 6/16 (38%) LOH present/MEN1 WT tumors and in 1/21 (5%) LOH absent/MEN1 altered tumors (p < 0.0001). The mean Ki-67 index of LOH present/MEN1 WT tumors was 22% and that of LOH absent/MEN1 altered tumors was 9%. Conclusions: This is the first study to report widespread somatic LOH in metastatic WD panNETs. PanNETs appear to exhibit more LOH overall than virtually any tumor type studied. In this cohort, LOH was a prognostic marker of inferior OS and was associated with more aggressive pathologic features. LOH warrants further investigation as it may help better characterize these clinically heterogeneous tumors.

scholarly journals Spectrum of DICER1 Germline Pathogenic Variants in Ovarian Sertoli–Leydig Cell Tumor

2021 ◽  
Vol 10 (9) ◽  
pp. 1845
Author(s):  
Elisa De Paolis ◽  
Rosa Maria Paragliola ◽  
Paola Concolino
Keyword(s):  
Leydig Cell ◽  
Case Reports ◽  
Molecular Genetic ◽  
Young Female ◽  
Micro Rna ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Genetic Features ◽  
Dicer1 Syndrome ◽  
Significant Discovery

Sertoli–Leydig Cell Tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms, which predominantly affect adolescents and young female adults. The SLCTs clinical diagnosis and treatment remains challenging due to the rarity and the varied presentation. A large majority of SLCTs are unilateral, but also bilateral neoplasms have been reported, sometimes in the context of DICER1 syndrome. In fact, the most significant discovery regarding the molecular genetics basis of SLCTs was the finding of somatic and germline pathogenic variants in the DICER1 gene. The DICER1 protein is a key component of the micro-RNA processing pathway. Germline DICER1 pathogenic variants are typically inherited in an autosomal dominant pattern and are most often loss-of-function variants dispersed along the length of the gene. Contrarily, DICER1-related tumors harbor a characteristic missense “RNase IIIb hotspot” mutation occurring in trans, or, less frequently, loss of heterozygosity (LOH) event involving the wild-type allele. While DICER1 mutations have been identified in approximately 60% of SLCTs, especially in the moderately or poorly differentiated types, there are only a few case reports of ovarian SLCT with underlying germline DICER1 mutations. In this review, we focus on the molecular genetic features of SLCT, performing an extensive survey of all germline pathogenic variants modifying the whole sequence of the DICER1 gene. We point out that DICER1 genetic testing, coupled with an accurate variants classification and timely counseling, is of crucial importance in the clinical management of ovarian SLCT-affected patients.

scholarly journals Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1351
Author(s):  
Ibolya Czegle ◽  
Austin L. Gray ◽  
Minjing Wang ◽  
Yan Liu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Molecular Genetic ◽  
Hematologic Malignancies ◽  
Genetic Alterations ◽  
World Health ◽  
Lymphoid Tissues ◽  
Prognostic Information ◽  
Genetic Changes ◽  
Plasma Cell Neoplasms ◽  
Health Organization

Hematologic malignancies are known to be associated with numerous cytogenetic and molecular genetic changes. In addition to morphology, immunophenotype, cytochemistry and clinical characteristics, these genetic alterations are typically required to diagnose myeloid, lymphoid, and plasma cell neoplasms. According to the current World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, numerous genetic changes are highlighted, often defining a distinct subtype of a disease, or providing prognostic information. This review highlights how these molecular changes can alter mitochondrial bioenergetics, cell death pathways, mitochondrial dynamics and potentially be related to mitochondrial genetic changes. A better understanding of these processes emphasizes potential novel therapies.

Sign in / Sign up

Export Citation Format

Share Document