Somatic activating ARAF mutations in Langerhans cell histiocytosis

Blood ◽  
2014 ◽  
Vol 123 (20) ◽  
pp. 3152-3155 ◽  
Author(s):  
David S. Nelson ◽  
Willemijn Quispel ◽  
Gayane Badalian-Very ◽  
Astrid G. S. van Halteren ◽  
Cor van den Bos ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Langerhans Cell Histiocytosis ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Novel Mutations ◽  
Whole Exome ◽  
Key Points ◽  
Inhibitor Treatment

Key Points Whole exome sequencing reveals novel mutations in ARAF that activate the kinase and are inhibitable by vemurafenib in a patient with LCH. Requiring the presence of BRAF V600E in LCH to qualify for rat fibrosarcoma inhibitor treatment may be overly exclusionary.

scholarly journals BRAF-V600E–mutated Rosai-Dorfman-Destombes disease and Langerhans cell histiocytosis with response to BRAF inhibitor

2019 ◽  
Vol 3 (12) ◽  
pp. 1848-1853 ◽  
Author(s):  
Rosemarie Mastropolo ◽  
Allison Close ◽  
Steven W. Allen ◽  
Kenneth L. McClain ◽  
Scott Maurer ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Braf Inhibitor ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Disease Monitoring ◽  
Blood Testing ◽  
Molecular Assays ◽  
Key Points ◽  
Treatment Plans ◽  
Inhibitor Treatment

Key Points Demonstration of BRAF-V600E in Rosai-Dorfman-Destombes disease requires sensitive molecular assays and molecular-based tissue immunostain. BRAF-V600E blood testing is important for disease-monitoring BRAF-mutated histiocytosis and can guide inhibitor treatment plans.

A Case of Pulmonary Langerhans Cell Sarcoma Simultaneously Diagnosed with Cutaneous Langerhans Cell Histiocytosis Studied by Whole-Exome Sequencing

2017 ◽  
Vol 138 (1) ◽  
pp. 24-30 ◽  
Author(s):  
Si-Wook Kim ◽  
Moon Ki Choi ◽  
Hye Sook Han ◽  
Hyojin Song ◽  
Youngil Koh ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Langerhans Cell Histiocytosis ◽  
Tp53 Gene ◽  
Langerhans Cell ◽  
Cell Sarcoma ◽  
Langerhans Cell Sarcoma ◽  
Whole Exome ◽  
Pathological Review ◽  
Cytological Features

Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS) are clonal proliferations of Langerhans-type cells. Unlike in LCH, the pathophysiology and clinical course of LCS are unclear due to its rarity. Here, we report the case of a 73-year-old male patient who was diagnosed with cutaneous LCH and pulmonary LCS at the same time. Pathological review of these 2 tumors revealed similar immunohistochemical findings. However, the tumor cells in LCS had more aggressive cytological features than those in LCH. Results of BRAF mutation analysis using real-time PCR were negative for both tumors. In whole-exome sequencing (WES), stop-gain mutations in TP53 gene were discovered only in LCS cells. The mechanism of development of LCS from various progenitor cells is currently unclear. According to the results of the WES study, changes in TP53 gene might have contributed to the malignant features of LCS.

scholarly journals High prevalence of somatic MAP2K1 mutations in BRAF V600E–negative Langerhans cell histiocytosis

Blood ◽  
2014 ◽  
Vol 124 (10) ◽  
pp. 1655-1658 ◽  
Author(s):  
Noah A. Brown ◽  
Larissa V. Furtado ◽  
Bryan L. Betz ◽  
Mark J. Kiel ◽  
Helmut C. Weigelin ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Genome Sequencing ◽  
High Frequency ◽  
Langerhans Cell Histiocytosis ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Braf Mutations ◽  
Key Points ◽  
High Prevalence

Key Points Targeted genome sequencing reveals high-frequency somatic MAP2K1 mutations in Langerhans cell histiocytosis. MAP2K1 mutations are mutually exclusive with BRAF mutations and may have implications for the use of BRAF and MEK targeted therapy.

Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

2021 ◽  
Vol 22 ◽  
Author(s):  
Masoud Heidari ◽  
Hamid Gharshasbi ◽  
Alireza Isazadeh ◽  
Morteza Soleyman-Nejad ◽  
Mohammad Hossein Taskhiri ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Polycystic Kidney ◽  
Novel Mutations ◽  
Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

scholarly journals Whole exome sequencing normal BMI-NAFLD and obese type 3-non NAFLD phenotype in Saudi Arabian population reveals novel mutations

HPB ◽  
2019 ◽  
Vol 21 ◽  
pp. S70-S71
Author(s):  
F.A. AlSaif ◽  
M. Ahmed ◽  
M.A. AlOtaiby ◽  
H.S. AlMadany ◽  
M.A. AlMayouf
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Saudi Arabian ◽  
Novel Mutations ◽  
Whole Exome ◽  
Type 3 ◽  
Arabian Population

Identification of two novel mutations in three Chinese families with Kallmann syndrome using whole exome sequencing

Andrologia ◽  
2020 ◽  
Vol 52 (7) ◽  
Author(s):  
Qin Zhang ◽  
Hong‐hui He ◽  
Muhammad Usman Janjua ◽  
Fang Wang ◽  
You‐bo Yang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Kallmann Syndrome ◽  
Novel Mutations ◽  
Chinese Families ◽  
Whole Exome

scholarly journals A case of Langerhans cell sarcoma on the scalp: Whole‐exome sequencing reveals a role of ultraviolet in the pathogenesis

2020 ◽  
Vol 70 (11) ◽  
pp. 881-887
Author(s):  
Hiroyuki Katsuragawa ◽  
Yosuke Yamada ◽  
Yoshihiro Ishida ◽  
Yo Kaku ◽  
Masakazu Fujimoto ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Langerhans Cell ◽  
Cell Sarcoma ◽  
Langerhans Cell Sarcoma ◽  
Whole Exome

scholarly journals A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function

Blood ◽  
2015 ◽  
Vol 125 (11) ◽  
pp. 1822-1825 ◽  
Author(s):  
Marisa L. R. Cunha ◽  
Kamran Bakhtiari ◽  
Jorge Peter ◽  
J. Arnoud Marquart ◽  
Joost C. M. Meijers ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Bleeding Disorder ◽  
Factor V ◽  
East Texas ◽  
Gain Of Function ◽  
Whole Exome ◽  
Key Points

Key Points A novel gain-of-function mutation in factor V leading to increased levels of TFPI and bleeding was identified by whole exome sequencing. Factor V Amsterdam (F5 C2588G) resembles the mutation (F5 A2350G) leading to East Texas bleeding disorder.

scholarly journals Whole exome sequencing identifies three novel mutations inANTXR1in families with GAPO syndrome

2014 ◽  
Vol 164 (9) ◽  
pp. 2328-2334 ◽  
Author(s):  
Yavuz Bayram ◽  
Davut Pehlivan ◽  
Ender Karaca ◽  
Tomasz Gambin ◽  
Shalini N. Jhangiani ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutations ◽  
Whole Exome

scholarly journals IMPACT: a whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples

2016 ◽  
Vol 23 (4) ◽  
pp. 721-730 ◽  
Author(s):  
Jennifer Hintzsche ◽  
Jihye Kim ◽  
Vinod Yadav ◽  
Carol Amato ◽  
Steven E Robinson ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Impact Analysis ◽  
Resistance Mutation ◽  
Braf Inhibitor ◽  
Egfr Mutations ◽  
Analysis Pipeline ◽  
Whole Exome ◽  
The Impact ◽  
Inhibitor Treatment

Abstract Objective Currently, there is a disconnect between finding a patient’s relevant molecular profile and predicting actionable therapeutics. Here we develop and implement the Integrating Molecular Profiles with Actionable Therapeutics (IMPACT) analysis pipeline, linking variants detected from whole-exome sequencing (WES) to actionable therapeutics. Methods and materials The IMPACT pipeline contains 4 analytical modules: detecting somatic variants, calling copy number alterations, predicting drugs against deleterious variants, and analyzing tumor heterogeneity. We tested the IMPACT pipeline on whole-exome sequencing data in The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples with known EGFR mutations. We also used IMPACT to analyze melanoma patient tumor samples before treatment, after BRAF-inhibitor treatment, and after BRAF- and MEK-inhibitor treatment. Results IMPACT Food and Drug Administration (FDA) correctly identified known EGFR mutations in the TCGA lung adenocarcinoma samples. IMPACT linked these EGFR mutations to the appropriate FDA-approved EGFR inhibitors. For the melanoma patient samples, we identified NRAS p.Q61K as an acquired resistance mutation to BRAF-inhibitor treatment. We also identified CDKN2A deletion as a novel acquired resistance mutation to BRAFi/MEKi inhibition. The IMPACT analysis pipeline predicts these somatic variants to actionable therapeutics. We observed the clonal dynamic in the tumor samples after various treatments. We showed that IMPACT not only helped in successful prioritization of clinically relevant variants but also linked these variations to possible targeted therapies. Conclusion IMPACT provides a new bioinformatics strategy to delineate candidate somatic variants and actionable therapies. This approach can be applied to other patient tumor samples to discover effective drug targets for personalized medicine. IMPACT is publicly available at http://tanlab.ucdenver.edu/IMPACT.

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