scholarly journals CSF3R T618I, SETBP1 G870S, SRSF2 P95H, and ASXL1 Q780* tetramutation co-contribute to myeloblast transformation in a chronic neutrophilic leukemia

2021 ◽  
Author(s):  
Yi Qian ◽  
Yan Chen ◽  
Xiaoming Li
Keyword(s):  
Alpha Interferon ◽  
Past Medical History ◽  
Variant Allele Frequency ◽  
Significant Past Medical History ◽  
Chronic Neutrophilic Leukemia ◽  
Hypercellular Marrow ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Stat Pathway

AbstractChronic neutrophilic leukemia (CNL) is a rare but serious myeloid malignancy. In a review of reported cases for WHO-defined CNL, CSF3R mutation is found in about 90% cases and confirmed as the molecular basis of CNL. Concurrent mutations are observed in CSF3R-mutated CNL patients, including ASXL1, SETBP1, SRSF2, JAK2, CALR, TET2, NRAS, U2AF1, and CBL. Both ASXL1 and SETBP1 mutations in CNL have been associated with a poor prognosis, whereas, SRSF2 mutation was undetermined. Our patient was a 77-year-old man and had no significant past medical history and symptoms with leukocytosis. Bone marrow (BM) aspirate and biopsy revealed a markedly hypercellular marrow with prominent left-shifted granulopoiesis. Next-generation sequencing (NGS) of DNA from the BM aspirate of a panel of 28 genes, known to be pathogenic in MDS/MPN, detected mutations in CSF3R, SETBP1, and SRSF2, and a diagnosis of CNL was made. The patient did not use a JAK-STAT pathway inhibitor (ruxolitinib) but started on hydroxyurea and alpha-interferon and developed pruritus after 4 months of diagnosis and nasal hemorrhage 1 month later. Then, the patient was diagnosed with CNL with AML transformation and developed intracranial hemorrhage and died. We repeated NGS and found that three additional mutations were detected: ASXL1, PRKDC, MYOM2; variant allele frequency (VAF) of the prior mutations in CSF3R, SETBP1, and SRSF2 increased. The concurrence of CSF3RT618I, ASXL1, SETBP1, and SRSF2 mutation may be a mutationally detrimental combination and contribute to disease progression and AML transformation, as well as the nonspecific treatment of hydroxyurea and alpha-interferon, but the significance and role of PRKDC and MYOM2 mutations were not undetermined.

Role of Ancillary Techniques in Biliary Cytopathology Specimens

2019 ◽  
Vol 64 (1-2) ◽  
pp. 175-181 ◽  
Author(s):  
Lester Layfield
Keyword(s):  
Mutational Analysis ◽  
Diagnostic Sensitivity ◽  
Individual Gene ◽  
Duct Systems ◽  
Brushing Cytology ◽  
Standard Of Practice ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Biliary brushing cytology has become the standard of practice for the investigation of strictures of the biliary and pancreatic duct systems. The methodology however has a limitation in that it has low diagnostic sensitivity when only cytologic evaluation is used. A number of testing methodologies have been applied to brushing specimens in an attempt to improve overall sensitivity without loss of specificity. These have included DNA ploidy analysis, immunocytochemistry, individual gene mutational analysis, fluorescence in-situ hybridization (FISH), and next generation sequencing (NGS). Currently, FISH coupled with routine cytology appears to be the method of choice for improving diagnostic sensitivity. NGS shows significant promise for improvement of diagnostic sensitivity.

scholarly journals Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B

2020 ◽  
Vol 9 (10) ◽  
pp. 1042-1050
Author(s):  
Catherine Cardot Bauters ◽  
Emmanuelle Leteurtre ◽  
Bruno Carnaille ◽  
Christine Do Cao ◽  
Stéphanie Espiard ◽  
...  
Keyword(s):  
Germline Variant ◽  
Whole Exome ◽  
Familial Cancers ◽  
Heterozygous Variant ◽  
Unknown Significance ◽  
Next Generation Sequencing Ngs ◽  
Design And Methods ◽  
Generation Sequencing

Objective We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. Design and methods Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. Results A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. Conclusion In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

scholarly journals Potentially Actionable Targets: Evidence Standards for Credible Next Generation Sequencing Technology Assessment Claims

2017 ◽  
Vol 8 (3) ◽  
pp. 9
Author(s):  
Paul C Langley
Keyword(s):  
Next Generation Sequencing ◽  
Technology Assessment ◽  
Critical Issue ◽  
Evidence Base ◽  
Cost Of Care ◽  
Next Generation ◽  
Next Generation Sequencing Technology ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Despite considerable resources devoted to developing databases to support competitive credible claims for next generation sequencing (NGS) claims, we have yet to meet the standards required in health technology assessment to support such claims. The purpose of this commentary is to consider options open in establishing claims for NGS recommendations. Although NGS platforms offer potential promise in improving clinical outcomes, supporting cost-effectiveness and reducing the overall cost of care in target populations, this has yet to be demonstrated on a scale that is likely to satisfy reimbursers and health care decision makers. Issues addressed include (i) the importance of credible, evaluable and replicable claims from individual NGS platforms; (ii) the difficulties in moving beyond broad-brush claims for improved survival; (iii) the standards required for an NGS evidence base; (iv) protocol designs in establishing the independent contribution of NGS actionable therapy recommendations to outcomes claims; (v) the role of NGS registries; and (vi) protocols to support ongoing credible, evaluable and replicable claims in target patient populations. The critical issue is not analytical and clinical validity but clinical utility. This has yet to be demonstrated.   Type: Commentary

scholarly journals A cloud-based learning environment for comparing RNA-seq aligners

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 888
Author(s):  
Elizabeth Baskin ◽  
Peter DeFord ◽  
Allison F. Dennis ◽  
Ian Misner ◽  
Frederick J. Tan ◽  
...  
Keyword(s):  
Rna Seq ◽  
Data Intensive ◽  
Data Analyst ◽  
Analysis Process ◽  
Wet Lab ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Machine Image ◽  
Made In

The rapid rise of high-throughput, data intensive experimental techniques has thrust many biologists into the role of data analyst – a role many biologists feel ill equipped to fill. Novices often struggle to find the resources and expertise they need to analyze their experimental results in a wet-lab environment. To fill this need, we developed an educational resource as part of a National Center for Biotechnology Information (NCBI) hackathon. Using RNA-seq as a model, our tutorial guides new users through the steps of data analysis, while placing an emphasis on understanding the motivation behind choices made in the process. To advance the goal of providing a deeper understanding of the analysis process, we developed a new tool, bamDiff. bamDiff allows users to compare the performance of multiple RNA-seq aligners, allowing users to select the most appropriate aligner for the data in question and experimental end-goal. Our tutorial is accessible via a GitHub wiki, with associated data and software provided on an Amazon Machine Image (AMI), which can be completed at no cost to the user through the Amazon Educate Program. Following the hackathon, our tutorial was integrated into the October 2015 offering of NCBI NOW (Next Generation Sequencing (NGS) Online Workshop) a free online experience targeting individuals new to NGS analysis.

Next-generation sequencing (NGS) for personalized therapy in metastatic breast cancer: Selection of therapy and outcomes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23166-e23166
Author(s):  
Jessica Ribeiro Gomes ◽  
Raphael Brandao Moreira ◽  
Matheus Bongers Alessandretti ◽  
Marcelo Rocha De Sousa Cruz
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Next Generation Sequencing ◽  
Clinical Benefit ◽  
Metastatic Breast ◽  
Personalized Therapy ◽  
Genomic Alterations ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e23166 Background: Treatment for metastatic breast cancer (MBC) has been driven by hormone receptors, HER2 expressions or their absence. Resistance to therapy and progressive disease will occur and empirical chemotherapy lines usually are the next steps. We aim to analyze the role of next-generation sequencing (NGS) for a personalized therapy in metastatic breast cancer and its potential clinical benefit. Methods: We included patients diagnosed with MBC treated at Centro Oncologico Antonio Ermirio de Moraes – Brazil from April 2013 to December 2016. All patients had metastasis accessible for biopsy. The tumor tissue was stored in paraffin and then analyzed by NGS-based assay that identifies genomic alterations within 236 genes. Results: 19 patients with MBC were evaluated (10 triple-negative; 4 HER2-positive; 5 hormonal receptor positive/HER2-negative). The most frequent and relevant genomic alterations identified by NGS assay were in the following genes: 13 TP53 (68.4%); 4 ERBB2 (21%); 4 PTEN (21%); 4 FGFR (21%); 3 PIK3CA (15.8%); 2 BRCA (10.5%); 2 ATM (10.5%); 2 AKT (10.5%); 2 MYC (10.5%); 1 CCND1 (5.3%); and 1 KRAS (5.3%). The NGS assay was able to suggest further therapy in 16/19 patients (84%). The suggested therapies would not be an empirical option according to the cancer’s subtype in 12/16 patients (75%). Therapy could be personalized in nine patients, across multiple lines of therapies (median of 5th line, with a range of 1-14). Median PFS was 6 months, and 8/9 patients (90%) achieved an objective response with the treatment indicated by NGS. Therefore, the assay provided clinical benefit in 42% of patients. Conclusions: NGS panel identified potentially actionable alterations in the majority of patients with MBC (84%). The overall clinical benefit with use of NGS-based assay was 42%. Further studies are necessary to better evaluate the role of NGS for a personalized therapy in MBC.

DEFICIENCY OF LRBA: BIBLIOGRAPHICAL REVIEW AND CASE REPORT

2021 ◽  
Vol 100 (2) ◽  
pp. 192-203
Author(s):  
I.V. Kondratenko ◽  
◽  
S.S. Vakhlayrskaya ◽  
D.V. Rogozhin ◽  
◽  
...  
Keyword(s):  
Case Report ◽  
Genetic Basis ◽  
Clinical Manifestations ◽  
Main Role ◽  
Principles Of Treatment ◽  
The Subject ◽  
Next Generation Sequencing Ngs ◽  
Lrba Deficiency ◽  
Generation Sequencing

Since the description of the first primary immunodeficiencies (PIDs) in the 50–60s of the last century, they have been the subject of intensive research aimed at elucidating their etiology and finding effective treatments. The development of next-generation sequencing (NGS) methods made it possible to reveal the genetic basis of many new forms of PID, which were previously attributed to various syndromes due to their clinical and immunological characteristics. An example of such a PID is the LRBA (the lipopolysaccharide-responsive and beige-like anchor protein) deficiency, sometimes called LATAIE [LRBA deficiency with autoantibodies, regulatory T (Treg) cell defects, autoimmune infiltration, and enteropathy]. The article provides information on the main role of the LRBA molecule in the functions of immunocompetent cells, describes immunological disorders and clinical manifestations of LRBA deficiency and the principles of treatment of diseases. Two own observations of LRBA deficiency are presented.

scholarly journals What Is the Giant Wall Gecko Having for Dinner? Conservation Genetics for Guiding Reserve Management in Cabo Verde

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 599 ◽  
Author(s):  
Catarina Pinho ◽  
Bárbara Santos ◽  
Vanessa Mata ◽  
Mariana Seguro ◽  
Maria Romeiras ◽  
...  
Keyword(s):  
Diet Composition ◽  
Taxonomic Resolution ◽  
Faecal Pellets ◽  
Cabo Verde ◽  
Reserve Management ◽  
Conservation Actions ◽  
Conservation Plans ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Knowledge on diet composition of a species is an important step to unveil its ecology and guide conservation actions. This is especially important for species that inhabit remote areas within biodiversity hotspots, with little information about their ecological roles. The emblematic giant wall gecko of Cabo Verde, Tarentola gigas, is restricted to the uninhabited Branco and Raso islets, and presents two subspecies. It is classified as Endangered, and locally Extinct on Santa Luzia Island; however, little information is known about its diet and behaviour. In this study, we identified the main plant, arthropods, and vertebrates consumed by both gecko subspecies using next generation sequencing (NGS) (metabarcoding of faecal pellets), and compared them with the species known to occur on Santa Luzia. Results showed that plants have a significant role as diet items and identified vertebrate and invertebrate taxa with higher taxonomic resolution than traditional methods. With this study, we now have data on the diet of both subspecies for evaluating the reintroduction of this threatened gecko on Santa Luzia as potentially successful, considering the generalist character of both populations. The information revealed by these ecological networks is important for the development of conservation plans by governmental authorities, and reinforces the essential and commonly neglected role of reptiles on island systems.

scholarly journals The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

2020 ◽  
Vol 52 (06) ◽  
pp. 427-434
Author(s):  
Jung Soo Lim ◽  
William E. Rainey
Keyword(s):  
Gene Mutations ◽  
Normal Subjects ◽  
Secondary Hypertension ◽  
Cell Clusters ◽  
Somatic Gene ◽  
Aldosterone Production ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Made In

AbstractPrimary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.

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