Mixed Pulmonary Adenocarcinoma and Atypical Carcinoid: A Report of Two Cases of a Non-codified Entity With Biological Profile

Pulmonary carcinoids combined with a non-neuroendocrine component have rarely been described, and this histological subtype is not included as a specific entity in the current World Health Organization classification of pulmonary neoplasms. Here, we described the molecular and histological features of two rare cases of mixed lung neoplasms, composed of atypical carcinoid and adenocarcinoma. The targeted next-generation sequencing analysis covering single nucleotide variations, copy number variations, and transcript fusions in a total of 161 cancer genes of the two different tumor components shows a similar molecular profile of shared and private gene mutations. These findings suggest their monoclonal origin from a transformed stem/progenitor tumor cell, which acquires a divergent differentiation during its development and progression and accumulates novel, specific mutations.

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Diffuse Gliomas for Nonneuropathologists: The New Integrated Molecular Diagnostics

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0449-ra ◽

2018 ◽

Vol 142 (7) ◽

pp. 804-814 ◽

Cited By ~ 10

Author(s):

Sunhee C. Lee

Keyword(s):

Krebs Cycle ◽

Diagnostic Algorithm ◽

World Health ◽

Wild Type ◽

Targeted Next Generation Sequencing ◽

Idh Mutations ◽

Diffuse Gliomas ◽

Conventional Histology ◽

Krebs Cycle Enzymes ◽

Health Organization

Diffuse gliomas comprise the bulk of “brain cancer” in adults. The recent update to the 4th edition of the World Health Organization's classification of tumors of the central nervous system reflects an unprecedented change in the landscape of the diagnosis and management of diffuse gliomas that will affect all those involved in the management and care of patients. Of the recently discovered gene alterations, mutations in the Krebs cycle enzymes isocitrate dehydrogenases (IDHs) 1 and 2 have fundamentally changed the way the gliomas are understood and classified. Incorporating information on a few genetic parameters (IDH, ATRX and/or p53, and chromosome 1p19q codeletion), a relatively straightforward diagnostic algorithm has been generated with robust and reproducible results that correlate with patients' survival far better than relying on conventional histology alone. Evidence also supports the conclusion that the vast majority of diffuse gliomas without IDH mutations (IDH–wild-type astrocytomas) behave like IDH–wild-type glioblastomas (“molecular GBM”). Together, these changes reflect a big shift in the practice of diagnostic neuropathology in which tumor risk stratification aligns better with molecular information than histology/grading. The purpose of this review is to provide the readers with a brief synopsis of the changes in the 2016 World Health Organization update with an emphasis on diffuse gliomas and to summarize key gene abnormalities on which these classifications are based. Practical points involved in day-to-day diagnostic workup are also discussed, along with a comparison of the various diagnostic tests, including immunohistochemistry, with an emphasis on targeted next-generation sequencing panel technology as a future universal approach.

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Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups

Cancers ◽

10.3390/cancers12102753 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2753 ◽

Cited By ~ 1

Author(s):

Giovanni Centonze ◽

Davide Biganzoli ◽

Natalie Prinzi ◽

Sara Pusceddu ◽

Alessandro Mangogna ◽

...

Keyword(s):

Next Generation Sequencing ◽

World Health Organization ◽

World Health ◽

Neuroendocrine Neoplasms ◽

Sequencing Analysis ◽

Next Generation ◽

Typical Carcinoid ◽

Mutational Status ◽

Health Organization ◽

Generation Sequencing

Lung neuroendocrine neoplasms (LNENs) represent a rare and heterogeneous population of lung tumors. LNENs incidence rate has increased dramatically over the past 30 years. The current World Health Organization LNENs classification (WHO 2015), distinguished four LNENs prognostic categories, according to their morphology, necrosis amount and mitotic count: typical carcinoid (TC), atypical-carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). At present, due to their rarity and biological heterogeneity there is still no consensus on the best therapeutic approach. Next-generation-sequencing analysis showed that WHO 2015 LNENs classes, could be characterized also by specific molecular alterations: frequently mutated genes involving chromatin remodeling and generally characterized by low mutational burden (MB) are frequently detected in both TC and AC; otherwise, TP53 and RB1 tumor suppressor genes alterations and high MB are usually detected in LCNEC and SCLC. We provide an overview concerning gene mutations in each WHO 2015 LNENs class in order to report the current LNENs mutational status as potential tool to better understand their clinical outcome and to drive medical treatment.

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Isocitrate dehydrogenase 1and 2 gene mutation status– a critical parameter in the diagnosis and prognosis of adult gliomas

Journal of Pathology of Nepal ◽

10.3126/jpn.v11i1.28992 ◽

2021 ◽

Vol 11 (1) ◽

pp. 1881-1885

Author(s):

Poornima Vijayan ◽

Laila Ilias ◽

Anupama Ponniah

Keyword(s):

Isocitrate Dehydrogenase ◽

Treatment Strategies ◽

Gene Mutations ◽

World Health ◽

Isocitrate Dehydrogenase 1 ◽

Similar Treatment ◽

Mutation Status ◽

Diagnosis And Prognosis ◽

The Central Nervous System ◽

Health Organization

Isocitrate dehydrogenase 1 and 2 mutations are known to be early events in gliomagenesis and have a definite role in tumor progression.Isocitrate dehydrogenase1/2 mutation status is considered to be one of the most powerful independent positive predictor of outcome amongst all molecular markers described in association with gliomas. The inclusion of this parameter in the 2016 update of the World Health Organization Classification of Tumors of The Central Nervous System reinforced its importance in glioma classification and prognostication. As a result, now there is enough evidence to prove that Isocitrate dehydrogenase-mutant and Isocitrate dehydrogenase- wildtypegliomas are two biologically distinct categories of gliomas with likely different pathways of tumorigenesis, different clinical outcomes, and respond differently to similar treatment strategies. Increasing knowledge aboutthe role of IDH1/2 mutation in gliomagenesis has resulted in many novel targeting strategies being developed and evaluated forusefulness in the clinical setting. This literature review aims to highlight the diagnostic and prognostic importance of Isocitrate dehydrogenase1/2 gene mutations in adult gliomas.

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Oligomonocytic and overt chronic myelomonocytic leukemia show similar clinical, genomic, and immunophenotypic features

Blood Advances ◽

10.1182/bloodadvances.2020002206 ◽

2020 ◽

Vol 4 (20) ◽

pp. 5285-5296 ◽

Cited By ~ 1

Author(s):

Xavier Calvo ◽

Nieves Garcia-Gisbert ◽

Ivonne Parraga ◽

Joan Gibert ◽

Lourdes Florensa ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Molecular Data ◽

Chronic Myelomonocytic Leukemia ◽

World Health ◽

Lower Percentage ◽

Molecular Profile ◽

Monocyte Count ◽

Blood Monocytes ◽

Health Organization ◽

Myelomonocytic Leukemia

Abstract Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDSs) or myelodysplastic/myeloproliferative neoplasms, unclassifiable with relative monocytosis (≥10% monocytes) and a monocyte count of 0.5 to <1 × 109/L. These patients show clinical and genomic features similar to those of overt chronic myelomonocytic leukemia (CMML), although most of them are currently categorized as MDS, according to the World Health Organization 2017 classification. We analyzed the clinicopathologic features of 40 patients with OM-CMML with well-annotated immunophenotypic and molecular data and compared them to those of 56 patients with overt CMML. We found similar clinical, morphological, and cytogenetic features. In addition, OM-CMML mirrored the well-known complex molecular profile of CMML, except for the presence of a lower percentage of RAS pathway mutations. In this regard, of the different genes assessed, only CBL was found to be mutated at a significantly lower frequency. Likewise, the OM-CMML immunophenotypic profile, assessed by the presence of >94% classical monocytes (MO1s) and CD56 and/or CD2 positivity in peripheral blood monocytes, was similar to overt CMML. The MO1 percentage >94% method showed high accuracy for predicting CMML diagnosis (sensitivity, 90.7%; specificity, 92.2%), even when considering OM-CMML as a subtype of CMML (sensitivity, 84.9%; specificity, 92.1%) in our series of 233 patients (39 OM-CMML, 54 CMML, 23 MDS, and 15 myeloproliferative neoplasms with monocytosis and 102 reactive monocytosis). These results support the consideration of OM-CMML as a distinctive subtype of CMML.

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Profiling of Somatic Mutations in Phaeochromocytoma and Paraganglioma by Targeted Next Generation Sequencing Analysis

International Journal of Endocrinology ◽

10.1155/2015/138573 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 33

Author(s):

Andrea Luchetti ◽

Diana Walsh ◽

Fay Rodger ◽

Graeme Clark ◽

Tom Martin ◽

...

Keyword(s):

Next Generation Sequencing ◽

Somatic Mutations ◽

Human Cancer ◽

Sequencing Analysis ◽

Cancer Genes ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Next Generation Sequencing Analysis ◽

Sequencing Strategy ◽

Generation Sequencing

At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127,andVHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations inHRAS, HIF2A, NF1, RET,andVHLhave been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse “mutation hotspots” in 50 human cancer genes. Mutations were identified forHRAS(c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); forBRAF(c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and forTP53(c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and noHRAS, BRAF, orTP53mutations occurred in this group. Combining our data with previous reports ofHRASmutations in PCC/PGL we find that the mean frequency ofHRAS/BRAFmutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting thatHRAS/BRAFmutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence forBRAFmutations in the pathogenesis of PCC/PGL/HNPGL.

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Design and Validation of a Gene-Targeted, Next-Generation Sequencing Panel for Routine Diagnosis in Gliomas

Cancers ◽

10.3390/cancers11060773 ◽

2019 ◽

Vol 11 (6) ◽

pp. 773 ◽

Cited By ~ 6

Author(s):

Nicky D’Haene ◽

Bárbara Meléndez ◽

Oriane Blanchard ◽

Nancy De Nève ◽

Laetitia Lebrun ◽

...

Keyword(s):

Next Generation Sequencing ◽

Simultaneous Detection ◽

Growth Factor Receptor ◽

Copy Number Variations ◽

World Health ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Molecular Alterations ◽

Routine Diagnosis ◽

Generation Sequencing

The updated 2016 World Health Organization (WHO) classification system for gliomas integrates molecular alterations and histology to provide a greater diagnostic and prognostic utility than the previous, histology-based classification. The increasing number of markers that are tested in a correct diagnostic procedure makes gene-targeted, next-generation sequencing (NGS) a powerful tool in routine pathology practice. We designed a 14-gene NGS panel specifically aimed at the diagnosis of glioma, which allows simultaneous detection of mutations and copy number variations, including the 1p/19q-codeletion and Epidermal Growth Factor Receptor (EGFR) amplification. To validate this panel, we used reference mutated DNAs, nontumor and non-glioma samples, and 52 glioma samples that were previously characterized. The panel was then prospectively applied to 91 brain lesions. A specificity of 100% and sensitivity of 99.4% was achieved for mutation detection. Orthogonal methods, such as in situ hybridization and immunohistochemical techniques, were used for validation, which showed high concordance. The molecular alterations that were identified allowed diagnosis according to the updated WHO criteria, and helped in the differential diagnosis of difficult cases. This NGS panel is an accurate and sensitive method, which could replace multiple tests for the same sample. Moreover, it is a rapid and cost-effective approach that can be easily implemented in the routine diagnosis of gliomas.

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COVID-19 vaccine coverage and the necessity of its urgent development towards Omicron the new SARS CoV-2 B.1.1. 529 variant

GSC Biological and Pharmaceutical Sciences ◽

10.30574/gscbps.2021.17.3.0350 ◽

2021 ◽

Vol 17 (3) ◽

pp. 058-060

Author(s):

Laith Ghadhanfer Shareef

Keyword(s):

Vaccine Coverage ◽

Gene Mutations ◽

World Health ◽

Acquired Immunity ◽

Live Virus ◽

Increased Risk ◽

The Difference ◽

Health Organization ◽

Virus Isolates ◽

Original Virus

A SARS-CoV-2 variant belonging to Pango lineage B.1.1.529 with a significant number of S-gene mutations compared to the original virus was found in early November 2021. On 26th November 2021, the World Health Organization (WHO) designated the mutation as a variant of concern and assigned it the name Omicron. The difference is identified by 30 changes in the spike protein, three minor deletions, and one minor insertion, 15 of which are in the receptor-binding area. The Omicron variant is the most diverging variety discovered in substantial numbers so far during the pandemic, raising significant concerns that it may be associated with significant reductions in vaccination efficacy and an increased risk of reinfections. Omicron pseudo- or live virus isolates are urgently needed to understand better the virus's escape potential against both vaccination, and infection-acquired immunity is urgently required.

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The Role of Forkhead Box Proteins in Acute Myeloid Leukemia

Cancers ◽

10.3390/cancers11060865 ◽

2019 ◽

Vol 11 (6) ◽

pp. 865 ◽

Cited By ~ 3

Author(s):

Carmelo Gurnari ◽

Giulia Falconi ◽

Eleonora De Bellis ◽

Maria Teresa Voso ◽

Emiliano Fabiani

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Drug Sensitivity ◽

Gene Mutations ◽

World Health ◽

Hematological Neoplasms ◽

Forkhead Box ◽

Health Organization ◽

Acute Myeloid

Forkhead box (FOX) proteins are a group of transcriptional factors implicated in different cellular functions such as differentiation, proliferation and senescence. A growing number of studies have focused on the relationship between FOX proteins and cancers, particularly hematological neoplasms such as acute myeloid leukemia (AML). FOX proteins are widely involved in AML biology, including leukemogenesis, relapse and drug sensitivity. Here we explore the role of FOX transcription factors in the major AML entities, according to “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia”, and in the context of the most recurrent gene mutations identified in this heterogeneous disease. Moreover, we report the new evidences about the role of FOX proteins in drug sensitivity, mechanisms of chemoresistance, and possible targeting for personalized therapies.

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A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype—c.4096A > T

Journal of Pediatric Genetics ◽

10.1055/s-0039-1694964 ◽

2019 ◽

Vol 09 (01) ◽

pp. 040-043

Author(s):

Ahmet Burak Arslan ◽

Ayşe Gül Zamani ◽

Sevgi Pekcan ◽

Mahmut Selman Yıldırım

Keyword(s):

Cystic Fibrosis ◽

The United States ◽

Clinical Findings ◽

World Health ◽

Cftr Gene ◽

Sequencing Analysis ◽

Nucleotide Exchange ◽

Pathogenic Variants ◽

Health Organization ◽

Additional Value

AbstractCystic fibrosis is a chronic multisystemic disease originating from functional alterations in CFTR (cystic fibrosis transmembrane conductance regulator) protein. To date, more than 300 pathogenic variants have been described in the literature. However, the diagnosis of CF, which was thought to become easier after the CFTR gene was identified, became more complicated due to the enormous amount of variations. In this study, we present a patient whose clinical findings were consistent with cystic fibrosis (CF) and showed a homozygous missense change that is not previously reported in the CFTR gene as pathogenic. In the next-generation sequencing analysis, homozygous c.4096A > T single-nucleotide exchange (I1366F [p.Ile1366Phe], missense) was shown in both alleles of the patient' CFTR gene. According to our database analysis, this variant has not yet been previously reported (VarSome, ClinVar, MutationTaster, Ensembl, dbSNP, PubMed). We do consider the change as pathogenic since the patient's findings were compatible with CF and the data analysis was in favor of pathogenicity. The most recent consensus report published in 2017 emphasized the importance of CFTR gene analysis, and this study emphasizes the difficulties of associating CFTR gene variations with a clinical picture and constitutes a new data on the genotype–phenotype correlation of CFTR variants. Also, considering the frequency of CF (according to World Health Organization data, every 1 out of 2,000–3,000 infants is born with CF in European Union countries and every 1 out of 3,500 in the United States) as well as the increasing rate of molecular studies performed on CF patients worldwide, reporting novel variation has an additional value.

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Gliosarcoma – Clinico-pathology, Genetics and a Review of Rare Congenital Cases

European Oncology & Haematology ◽

10.17925/eoh.2009.05.1.20 ◽

2009 ◽

Vol 05 (01) ◽

pp. 20

Author(s):

Christopher Dunham ◽

Keyword(s):

World Health Organization ◽

Brain Tumours ◽

Poor Prognosis ◽

Genetic Data ◽

World Health ◽

Recent Analysis ◽

Molecular Profile ◽

Low Grade ◽

Who Grade ◽

Health Organization

Congenital brain tumours are rare. In general, they are preferentially located in the supratentorial compartment, and despite the occurrence of low-grade entities, these tumours are associated with a very poor prognosis. When strictly defined, the most common forms of congenital neoplasia are teratomas and astrocytomas. Among the astrocytomas, all grades (World Health Organization [WHO] I–IV) and many of the different subtypes are represented. This includes the most prognostically worrisome ‘diffusely infiltrating’ astrocytomas. Gliosarcomas are a variant of glioblastoma (i.e. WHO grade IV astrocytoma) that exhibits both malignant astrocytic (i.e. glioblastoma) and mesenchymal (i.e. sarcoma) components. Despite their bi-phasic histology, genetic analyses of adult gliosarcoma cases suggest not only a molecular profile similar to glioblastoma, but also a monoclonal histogenesis for the glial and sarcomatous elements. Congenital gliosarcomas are extremely rare, with only a handful of cases being described in the literature. Not surprisingly, therefore, detailed clinical, pathological and genetic data are limited. However, based on a recent analysis of congenital glioblastomas, congenital gliosarcomas may constitute an entity that is genetically and prognostically distinct from adult cases.

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