scholarly journals Frequent Occurrence of NRAS and BRAF Mutations in Human Acral Naevi

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 546 ◽  
Author(s):  
Philipp Jansen ◽  
Ioana Cosgarea ◽  
Rajmohan Murali ◽  
Inga Möller ◽  
Antje Sucker ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Gene Mutations ◽  
Diagnostic Value ◽  
Clinicopathological Parameters ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Targeted Next Generation Sequencing ◽  
Melanocytic Tumors ◽  
Frequent Mutations ◽  
Melanoma Subtypes

Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including n = 87 (67%) BRAF, n = 24 (18%) NRAS, and one (1%) MAP2K1 mutations. BRAF mutations were almost exclusively V600E (n = 86, 99%) and primarily found in junctional and compound naevi. NRAS mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E BRAF, KIT, NF1, and TERT promoter mutations, present in acral melanoma, were not identified. Our study identifies BRAF and NRAS mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities.

scholarly journals p53 and EGFR gene mutations in malignant tumors of the lung

2021 ◽  
Vol 62 (4) ◽  
pp. 28-34
Author(s):  
S. Yermekova ◽  
M. Orazgaliyeva ◽  
T. Goncharova ◽  
F. Rakhimbekova ◽  
E. Serik
Keyword(s):  
Lung Cancer ◽  
Lung Tumor ◽  
Malignant Tumors ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
P53 Gene ◽  
Diagnostic Value ◽  
Cancer Diagnostics ◽  
Egfr Mutations ◽  
Exon 19

Relevance: Increased incidence of lung cancer globally and in Kazakhstan, lack of screening in hereditary cases, high mortality, and low survival of patients necessitate the study of the molecular genetic causes of the disease. At present, gene mutation studies for lung cancer diagnostics are expanding. However, many gene mutations revealed remain undercovered in the scientific literature, and there is not enough data on their prognostic and diagnostic value. The purpose of the study was to discover the specifics of the р53 gene mutations and reveal the EGFR exon 19 deletions and exon 21 L858R mutations in malignant tumors of the lung of various histogenesis. Methods: The mutations were studied in tumors (200 samples) and adjacent tissue (200 samples) of patients with lung cancer (squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the lung) by polymerase chain reaction (PCR), electrophoresis, and EcoR1- and Pst1-restriction of samples after p53 gene fragments and cDNA amplification and mRNA revertase treatment. Another 263 lung cancer samples were evaluated by real-time PCR for EGFR exon 19 deletions and EGFR exon 21 L858R mutations. Results: The p53 gene was not expressed in 50% of SCC and adenocarcinoma of the lung samples. Restriction revealed p53 mRNA mutations in 100% of SCC and 75% of ADC samples. p53 exon-intron 5-6 was mutated in 50% of ADC and 70% of SCC samples, exon-intron 7-9 – in 60% of SCC cases. EGFR exons 19 and 21 mutations found in 65 of 263 lung tumor samples were associated with increased sensitivity to EGFR tyrosine kinase inhibitors. Conclusion: The p53 gene mutations revealed in most samples of SCC and ADC of the lung could be used to diagnose lung cancer and predict its severity. The identified EGFR mutations allow predicting the effectiveness of targeted therapy

scholarly journals The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI)

2021 ◽  
Vol 22 (8) ◽  
pp. 3826
Author(s):  
Lisa Elefanti ◽  
Carolina Zamuner ◽  
Paolo Del Fiore ◽  
Camilla Stagni ◽  
Stefania Pellegrini ◽  
...  
Keyword(s):  
Early Stage ◽  
Chromosomal Rearrangements ◽  
Gene Mutations ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Prognostic Features ◽  
Mutation Burden ◽  
Number Variation ◽  
Molecular Landscape ◽  
Gains And Losses

Acral melanoma (AM) is a rare and aggressive subtype of melanoma affecting the palms, soles, and nail apparatus with similar incidence among different ethnicities. AM is unrelated to ultraviolet radiation and has a low mutation burden but frequent chromosomal rearrangements and gene amplifications. Next generation sequencing of 33 genes and somatic copy number variation (CNV) analysis with genome-wide single nucleotide polymorphism arrays were performed in order to molecularly characterize 48 primary AMs of Italian patients in association with clinicopathological and prognostic features. BRAF was the most commonly mutated gene, followed by NRAS and TP53, whereas TERT promoter, KIT, and ARID1A were less frequently mutated. Gains and losses were recurrently found in the 1q, 6p, 7, 8q, 20 and 22 chromosomes involving PREX2, RAC1, KMT2C, BRAF, CCND1, TERT, and AKT3 genes, and in the 6q, 9, 10, 11q and 16q chromosomes including CDKN2A, PTEN, and ADAMTS18 genes, respectively. This study confirmed the variety of gene mutations and the high load of CNV in primary AM. Some genomic alterations were associated with histologic prognostic features. BRAF mutations, found with a higher rate than previously reported, correlated with a low Breslow thickness, low mitotic count, low CNV of the AMs, and with early-stage of disease.

scholarly journals GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Philipp Jansen ◽  
Hansgeorg Müller ◽  
Georg C. Lodde ◽  
Anne Zaremba ◽  
Inga Möller ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Vascular Malformations ◽  
Gene Mutations ◽  
Kaposi’S Sarcoma ◽  
Diagnostic Value ◽  
Vascular Tumors ◽  
Malignant Neoplasms ◽  
Mutation Status ◽  
Targeted Next Generation Sequencing ◽  
Three Samples

Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi’s sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi’s sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in GNA genes, including GNA14 Q205, GNA11 and GNAQ Q209 were identified in 16 of 64 benign vascular tumors (25%). GNA gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating RAS mutations (HRAS and NRAS) were identified in three samples (16%). No activating GNA or RAS gene mutations were identified in Kaposi’s sarcomas. Our study identifies GNA14 Q205, GNA11 and GNAQ Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.

scholarly journals Mutation Profile of Aggressive Pheochromocytoma and Paraganglioma with Comparison of TCGA Data

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2389
Author(s):  
Yun Mi Choi ◽  
Jinyeong Lim ◽  
Min Ji Jeon ◽  
Yu-Mi Lee ◽  
Tae-Yon Sung ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
The Cancer Genome Atlas ◽  
Sequencing Analysis ◽  
Poor Overall Survival ◽  
Sdhb Mutation ◽  
Targeted Next Generation Sequencing ◽  
Mutation Profile ◽  
Next Generation Sequencing Analysis ◽  
Number Variation ◽  
Frequent Mutations

In pheochromocytoma and paraganglioma (PPGL), germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. However, the peculiar genetic events that drive the aggressive behavior including metastasis in PPGL are poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. A total of 115 germline and 34 somatic variants were identified with a median 0.58 per megabase tumor mutation burden in our cohort. The most frequent mutation was SDHB germline mutation (27%) and the second frequent mutations were somatic mutations for SETD2, NF1, and HRAS (13%, respectively). Patients were subtyped into three categories based on the kind of mutated genes: pseudohypoxia (n = 5), kinase (n = 5), and unknown (n = 5) group. In copy number variation analysis, deletion of chromosome arm 1p harboring SDHB gene was the most frequently observed. In our cohort, SDHB mutation and pseudohypoxia subtype were significantly associated with poor overall survival. In conclusion, subtyping of mutation profile can be helpful in aggressive PPGL patients with heterogeneous prognosis to make relevant follow-up plan and achieve proper treatment.

scholarly journals Increased STIP1 and Hsp90 Correlate with Progression and Prognosis of Lung Adenocarcinoma

2021 ◽  
Author(s):  
Biaoxue Rong ◽  
Youwen Zhang ◽  
Junye Wang ◽  
Shucheng Ye ◽  
Maoqing Guo ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Malignant Tumors ◽  
Clinical Stage ◽  
A549 Cells ◽  
Biological Behavior ◽  
Prognostic Indicators ◽  
Normal Lung ◽  
Clinicopathological Parameters ◽  
Strong Positive Correlation ◽  
Advanced Clinical Stage

Abstract Background: Stress-inducible phosphoprotein 1 (STIP1) and heat shock protein 90 (Hsp90) have been found to be correlated with malignant tumors. The aim of this investigation was to study the relationship between their expressions and lung adenocarcinoma (LAC). Methods: The expressions of STIP1and Hsp90 in LAC cells and tissues were tested by immunohistochemistry and western blot; the correlation between their expressions and clinicopathological parameters of LAC was analyzed by survival analysisand multiple regression analysis. Results: Expressions of STIP1 and Hsp90 were higher in A549 cells and LAC tissues than that in 16 human bronchial epithelial cells (16HBE cells) (P<0.05) and adjacent normal lung tissues (P < 0.05). The expression of STIP1 and Hsp90 in LAC showed a strong positive correlation (P < 0.05) and significantly correlated with lymph node metastasis (P < 0.05), advanced clinical stage (P < 0.05) and shorter survival (P < 0.05) of LAC. Conclusions: Increased expressions of STIP1 and Hsp90 were closely related to malignant biological behavior of LAC, suggesting that they could be used as potential biomarkers and prognostic indicators for LAC.

scholarly journals High throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes

2016 ◽  
Author(s):  
Marta R. Hidalgo ◽  
Cankut Cubuk ◽  
Alicia Amadoz ◽  
Francisco Salavert ◽  
José Carbonell-Caballero ◽  
...  
Keyword(s):  
High Throughput ◽  
Gene Mutations ◽  
Diagnostic Value ◽  
Therapeutic Interventions ◽  
Biological Knowledge ◽  
Individual Gene ◽  
Main Challenge ◽  
Activity Measurements ◽  
Cancer Types ◽  
Or Gene

AbstractUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.

scholarly journals Mitochondrial changes in carcinogenesis as a goal of antitumor therapy (review)

2020 ◽  
pp. 65-73
Author(s):  
T. E. Potemina ◽  
E. V. Guzikov
Keyword(s):  
Malignant Tumors ◽  
Gene Mutations ◽  
Cancer Development ◽  
Antitumor Therapy ◽  
Mutation Theory ◽  
Main Variant

Causes and mechanisms of cancer development are currently one of the urgent problems of medicine. The main variant for today is the mutation theory. Identification of the system of gene mutations, including in mitochondria, leading to this or that type of tumors, made it possible to develop a personalized, so-called targeting, the therapy of malignant tumors.

scholarly journals Characteristics of the mutation spectrum identified by comprehensive investigation of the CFTR gene in the Russian patients

2019 ◽  
Vol 47 (1) ◽  
pp. 38-46
Author(s):  
N. V. Petrova ◽  
A. Yu. Marakhonov ◽  
T. A. Vasilyeva ◽  
N. Yu. Kashirskaya ◽  
E. I. Kondratyeva ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Hereditary Disease ◽  
Mutation Spectrum ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Sequencing Method ◽  
Novel Variants ◽  
Frequent Mutations ◽  
Large Rearrangements

Rationale: Cystic fibrosis (CF; OMIM 219700) is a  common hereditary disease caused by mutations in the CFTR gene (OMIM 602421). The distribution and frequencies of the CFTR gene mutations vary considerably between countries and ethnic groups. By now about 11%  alleles of the CFTR gene remain unidentified after testing for frequent mutations in the Russian patients. A full determination of the mutation spectrum in the CFTR gene is necessary to optimize medical and genetic assistance to the population and to implement the achievements of targeted therapy in the treatment of CF patients.Materials and methods: The sample included 121 Russian CF patients, in whom testing for 34 routinely analyzed mutations did not identify one (n = 107) or both (n = 14) mutant alleles. Assessment of the coding sequence of the CFTR gene, including the regions of exon-intron junctions, 5’- and 3’-untranslated regions was performed by the Sanger sequencing method; in addition, the search for large rearrangements was conducted by the multiplex ligation-dependent probe amplification (MLPA) method.Results: In addition to the previously identified, 88  more variants were determined, including 28  missense mutations, 15  nonsense mutations, 18 frameshift mutations (14 deletions, 4  insertions), 14  splicing mutations, 1  in-frame insertion, 1  in-frame deletion, 1  in/del mutation, and 10  large rearrangements (7  deletions, 3  duplications). Twenty three (23) novel variants were sequenced. Four (4) complex mutant alleles were found. Sixty (60) variants are found once each. One hundred and thirty four (134) of 135 tested mutant alleles were identified.Conclusion: Consequent use of the sequencing and MLPA methods has allowed for identification of a high proportion of the tested mutant alleles in CF patients from Russia (134/135, > 99%), to detect a  significant diversity of the CFTR mutation spectrum (88  additional variants, 32  of them novel), a  number of repeated mutations (c.2353C>T, c.1240_1244delCAAAA, c.1766+1G>A and c.3929G>A) encountered in 5 or more unrelated patients, which could be included in the panel of routinely analyzed variants in the Russian CF patients; and a high proportion of large rearrangements of the CFTR gene. 

scholarly journals The Frequency of Familial Mediterranean Fever Gene Mutations and the Correlations between Phenotype and Genotype in Turkish Children

2020 ◽  
pp. 20-26
Author(s):  
Hakan Erdogan ◽  
Ayse Cavidan Sonkur ◽  
Orhan Görükmez ◽  
Ayse Erdogan ◽  
Dilek Damla Saymazlar ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Mutation Screening ◽  
Mefv Gene ◽  
Gene Mutations ◽  
Retrospective Case ◽  
Turkish Children ◽  
Pathogenic Variants ◽  
Frequent Mutations ◽  
Training And Research ◽  
Mediterranean Fever

Aim: Familial Mediterranian Fever is an autosomal recessive disease characterized by recurrent inflammatory attacks of serosal membranes. The aim of the current study was to determine the frequency of the Mediterranean fever (MEFV) gene pathogenic variants in 158 children (78 male, 80 female) diagnosed with Familial Mediterranean Fever (FMF) and to compare the phenotype-genotype correlation. Methods: In our retrospective case-control study, 158 FMF patients (78 males, 80 females) who were diagnosed with MEFV gene mutation in Bursa Yuksek Ihtisas Training and Research Hospital, Department of Pediatrics between January 2018 and June 2019 were included in the study.  Mutation screening of the MEFV gene was performed for 12 mutations and the 8 most common mutations were taken into the study. Results: Abdominal pain (77.8%), fever (74%) and arthralgia (46.2%) were the most prevalent clinical features in our patients. The most frequent mutations were M694V, E148Q, V726A, M680I and P369S. In cases with M694 mutation, it was noted that the incidence of arthritis was 2.5 times, appendectomy frequency 3.1 times higher, and early diagnosis probability 3.2 times higher. The frequency of chest pain was 2.9 times higher in the M680I mutation, and the frequency of arthralgia was 2.2 times higher in the P369S mutation. Conclusion: Patient’s mutations in FMF patients are important for clinical expectations, and some mutations such as P369S are not as innocent as expected. However, reevaluation of phenotypes of mutations that are rare with more patients will be significant. 

scholarly journals Histopathological characteristics and coexpression of p53 and p16INK4a proteins in renal cancer

2008 ◽  
Vol 65 (11) ◽  
pp. 820-824
Author(s):  
Sladjana Zivkovic ◽  
Milos Kostov ◽  
Svetlana Pavlovic ◽  
Zaklina Mijovic
Keyword(s):  
Significant Positive Correlation ◽  
Renal Carcinoma ◽  
Malignant Tumors ◽  
Immunohistochemical Analysis ◽  
P53 Mutation ◽  
Clinicopathological Parameters ◽  
Tumor Differentiation ◽  
Tissue Samples ◽  
Protein P53 ◽  
P16 Expression

Background/Aim. Renal carcinoma represents histologically heterogeneous group of malignant tumors, with various clinical aggressiveness. The frequency of p53 mutation in primal renal carcinoma is rare, although there are information about its heterogeneous accumulation. The loss of protein p16 expression in primal renal carcinoma is detected in 20-30% of the cases. The aim of this paper was to determine frequency of mutated protein p53 and expression of protein p16INK4a in renal carcinoma, to analyze their correlative relation and relation with the examined clinicopathological parameters. Methods. The examination included 12 patients (66.7% men, 33.3% women), with patohistologically verified renal carcinoma. Expression of mutated form of protein p53 and protein p16 was determined in tissue samples, by immunohistochemical analysis using of mice monoclonical antibodies produced by DAKO, Denmark. Results. In 9 (75%) of the cases was detected mutated protein p53, of whom 66.6% had higher histological gradus of tumor (G3-4) and higher pathological stadium of the disease (pT3a-b) at the same time. In 7 (58.3%) and 5 (41.7%) of the cases expression of protein p16, the loss of expression of protein p16 were detected respectively. A statistically significant positive correlation was determined between pathological stadium of disease (TNM) and the degree of tumor differentiation (G) (? = 0.834; p < 0.001), as well as between TNM and mitotic index (? = 0.622; p = 0.031). Conclusion. A mutated form of protein p53 exists in 75% of the cases with the renal carcinoma and 66.6% of then have higher histological gradus of tumor and higher stadium of tumor disease at the same time. Coexpression of mutated protein p53 and protein p16INK4a in renal carcinoma is not statistically significant and it is not in correlation with clinicopathological parameters. Immunohistochemical analysis of mutated protein p53 in renal carcinoma can have predictive significance.

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