Combination Of Gene Mutations Research Articles

Acute myeloid leukemia with a novel AKAP9::PDGFRA fusion transformed from essential thrombocythemia: A case report and mini review

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark CALR mutation transforming to AML characterized by a previously unreported AKAP9::PDGFRA fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.

Mathematical modeling the order of driver gene mutations in colorectal cancer.

Tumor heterogeneity is a large obstacle for cancer study and treatment. Different cancer patients may involve different combinations of gene mutations or the distinct regulatory pathways for inducing the progression of tumor. Investigating the pathways of gene mutations which can cause the formation of tumor can provide a basis for the personalized treatment of cancer. Studies suggested that KRAS, APC and TP53 are the most significant driver genes for colorectal cancer. However, it is still an open issue regarding the detailed mutation order of these genes in the development of colorectal cancer. For this purpose, we analyze the mathematical model considering all orders of mutations in oncogene, KRAS and tumor suppressor genes, APC and TP53, and fit it on data describing the incidence rates of colorectal cancer at different age from the Surveillance Epidemiology and End Results registry in the United States for the year 1973-2013. The specific orders that can induce the development of colorectal cancer are identified by the model fitting. The fitting results indicate that the mutation orders with KRAS → APC → TP53, APC → TP53 → KRAS and APC → KRAS → TP53 explain the age-specific risk of colorectal cancer with very well. Furthermore, eleven pathways of gene mutations can be accepted for the mutation order of genes with KRAS → APC → TP53, APC → TP53 → KRAS and APC → KRAS → TP53, and the alternation of APC acts as the initiating or promoting event in the colorectal cancer. The estimated mutation rates of cells in the different pathways demonstrate that genetic instability must exist in colorectal cancer with alterations of genes, KRAS, APC and TP53.

The targeted next-generation sequence revealed SMAD4, AKT1, and TP53 mutations from circulating cell-free DNA of breast cancer and its effect on protein structure – A computational approach

Breast cancer biomarkers that detect marginally advanced stages are still challenging. The detection of specific abnormalities, targeted therapy selection, prognosis, and monitoring of treatment effectiveness over time are all made possible by circulating free DNA (cfDNA) analysis. The proposed study will detect specific genetic abnormalities from the plasma cfDNA of a female breast cancer patient by sequencing a cancer-related gene panel (MGM455 – Oncotrack Ultima), including 56 theranostic genes (SNVs and small INDELs). Initially, we determined the pathogenicity of the observed mutations using PredictSNP, iStable, Align-GVGD, and ConSurf servers. As a next step, molecular dynamics (MD) was implemented to determine the functional significance of SMAD4 mutation (V465M). Lastly, the mutant gene relationships were examined using the Cytoscape plug-in GeneMANIA. Using ClueGO, we determined the gene’s functional enrichment and integrative analysis. The structural characteristics of SMAD4 V465M protein by MD simulation analysis further demonstrated that the mutation was deleterious. The simulation showed that the native structure was more significantly altered by the SMAD4 (V465M) mutation. Our findings suggest that SMAD4 V465M mutation might be significantly associated with breast cancer, and other patient-found mutations (AKT1-E17K and TP53-R175H) are synergistically involved in the process of SMAD4 translocate to nuclease, which affects the target gene translation. Therefore, this combination of gene mutations could alter the TGF-β signaling pathway in BC. We further proposed that the SMAD4 protein loss may contribute to an aggressive phenotype by inhibiting the TGF-β signaling pathway. Thus, breast cancer’s SMAD4 (V465M) mutation might increase their invasive and metastatic capabilities. Communicated by Ramaswamy H. Sarma

Multiplexed genome editing by in vivo electroporation of Cas9 ribonucleoproteins effectively induces endometrial carcinoma in mice.

Synergistic effects among multiple gene mutations are involved in cancer development and progression. However, developing genetically modified mouse models to analyze various combinations of mutations is extremely labor-intensive and time-consuming. To address these problems, we developed a novel method for in vivo multiplexed genome editing of the murine uterus to model human endometrial carcinoma (EMC). To do this, we injected a CRISPR-Cas9 ribonucleoprotein complex into the uterine cavity of adult female mice, followed by electroporation. Evaluation of reporter mice demonstrated that genome editing occurred specifically in uterine epithelial cells, which are the origin of EMCs. Simultaneous targeting of Pten/Trp53/Lkb1, or targeting of Pten/Lkb1 along with the Ctnnb1ΔEx3 mutation, resulted in efficient generation of invasive tumors in wild-type females within 3months. This novel method will enable rapid and easy validation of many combinations of gene mutations that lead to endometrial carcinogenesis.

Cystic fibrosis and congenital adrenal hyperplasia: A rare occurrence with diagnostic dilemmas, similarities and contradictions

Cystic fibrosis (CF) is a hereditary syndrome composed of exocrine gland dysfunction involving multiple systems which if untreated may result in chronic respiratory infections, pancreatic enzyme deficiency and failure to thrive. The association between CF and other inherited diseases or congenital anomalies is rare. We describe a rare case of CF with concomitant congenital adrenal hyperplasia (CAH). 21- Hydroxylase deficiency accounts for most CAH cases. Varity in clinical phenotypes depends on the amount of enzymatic activity which in turn depends on different combination of gene mutations. The genes of CAH and CF are located in different locations. The chance of these diseases coexisting in our patient would be a rare combination. However, such a case will be more frequent in our population than others because of consanguineous marriage and common ancestors. There are diagnostic difficulties, similarities and contradictions between two diseases and they are pointed out.

Genetic algorithm efficiency improvement in the course of set cover problem solution

Introduction. Practical tasks (location of service points, creation of microcircuits, scheduling, etc.) often require an exact or approximate to exact solution at a large dimension. In this case, achieving an acceptable result requires solving a set cover problem, fundamental for combinatorics and the set theory. An exact solution can be obtained using exhaustive methods; but in this case, when the dimension of the problem is increased, the time taken by an exact algorithm rises exponentially. For this reason, the precision of approximate methods should be increased: they give a solution that is only approximate to the exact one, but they take much less time to search for an answer at a large dimension.Materials and Methods. One of the ways to solve the covering problem is described, it is a genetic algorithm. The authors use a modification of the Goldberg model and try to increase its efficiency through various types of mutation and crossover operators. We are talking about gene mutations, two-point mutations, addition and deletion mutations, insertion and deletion mutations, saltation, mutations based on inversion. The following types of crossover operator are noted: single-point, two-point, three-point and their versions with restrictions, uniform, triad. The effect of the stopping condition and the probability values of genetic operators on the accuracy of the solutions is investigated. It is shown how an increase in the number of individuals in a generation affects the efficiency of a solution. Research Results. The experiment results allow us to draw three conclusions. 1) It is recommended to use a combination of gene mutation and single-point crossing. 2) With an increase in the number of individuals, the accuracy of the result and the time to obtain it increases. The average deviation from the exact result at a task size of 25 × 25 was 0%, at 50 × 50 – 0%, at 75 × 75 – 0.013%, at 100 × 100 – 0%, at 110 × 110 – 0% (the number of individuals was 500).3) It is advisable to use the probabilities of the mutation and crossover operator 100% and 100%, respectively. Discussion and Conclusions. Recommendations are given to improve the efficiency of covering problem solution. To this end, a preferred combination of the genetic algorithm parameters, of types of crossover and mutation operators is indicated.

MOLECULAR-GENETIC MODELS FOR PROGNOSIS OF DEVELOPMENT OF TUMORS OF REPRODUCTIVE SYSTEM IN WOMEN WITH FAMILY HISTORY OF CANCER

To develop a prognostic molecular genetic model for assessing the risk of development of benign and malignant tumors of female reproductive organs (FRO) in patients from cancer-affected families. The work presents the data on a comprehensive clinical examination of 210women (90patients with FRO cancer with aggregation of tumor pathology in families, 65patients with benign pathology of FRO from cancer-affected families, 55women- control group of healthy women without family history of cancer). Clinical genealogical analysis, morphological examination of tumors and molecular genetic studies of genomic DNA from peripheral blood and tumors were carried out. It was established that in the families of patients with benign and malignant pathology of FRO, malignant tumors associated with Lynch II syndrome are observed. Based on the analysis of detected ESR-1, CYP2D6*4and mutations in BRCA1/2genes in cancer patients and in patients with benign pathology, molecular genetic models have been developed to assess the individual risk of development of benign and malignant tumors of FRO. It has been established that these molecular genetic models and combinations of gene mutations and gene polymorphisms (SNP) by the intergene interaction that was analyzed, were found to be reliable in assessing the risk of benign and malignant pathology of the mammary gland and ovary. The model, which included the polymorphic variants of the T397C(ESR1)/CYP2D6*4genes was of the best predictive accuracy for the evaluation of the risk of benign tumors of the FRO (71.68%) and the highest reliability (p < 0.001). At the same time, all identified models of intergene interaction in the development of malignant pathology of FRO were reliable, prognostically significant with high reproduction and almost identical accuracy (65.00-68.23%). The obtained results indicate a high informativeness of such molecular genetic indices as the polymorphism of ESR1and CYP2D6*4genes and mutations in BRCA1/2genes to assess the risk of benign or malignant tumors of FRO in families of patients with family history of cancer.

Flexible model-based clustering of mixed binary and continuous data: application to genetic regulation and cancer.

Clustering is used widely in ‘omics’ studies and is often tackled with standard methods, e.g. hierarchical clustering. However, the increasing need for integration of multiple data sets leads to a requirement for clustering methods applicable to mixed data types, where the straightforward application of standard methods is not necessarily the best approach. A particularly common problem involves clustering entities characterized by a mixture of binary data (e.g. presence/absence of mutations, binding, motifs and epigenetic marks) and continuous data (e.g. gene expression, protein abundance, metabolite levels). Here, we present a generic method based on a probabilistic model for clustering this type of data, and illustrate its application to genetic regulation and the clustering of cancer samples. We show that the resulting clusters lead to useful hypotheses: in the case of genetic regulation these concern regulation of groups of genes by specific sets of transcription factors and in the case of cancer samples combinations of gene mutations are related to patterns of gene expression. The clusters have potential mechanistic significance and in the latter case are significantly linked to survival. The method is available as a stand-alone software package (GNU General Public Licence) from http://github.com/BioToolsLeeds/FlexiCoClusteringPackage.git.

An overview of rare genetic disorders and recent diagnostic approaches

Genetic disorders are the leading causes of mortality and morbidity in humans. The prevalence of genetic diseases varies widely between different clusters depending on their organization, reproductive practices, and various other sociocultural factors. These disorders are mainly caused by mutations in monogenic, polygenic or the combination of gene mutations, consanguineous marriage practices, and environmental factors leading to damage of chromosomes. Nearly 7000 different types of rare genetic diseases/disorders are being discovered frequently. Cytogenetic and molecular techniques have been widely implicated to detect variations in the chromosomes and in genes. Several innovative and extremely robust methods for sequencing the nucleic acids such as next-generation sequencing have become available in the past few years for diagnosing chromosomal and genetic disorders. We have summarized the rare genetic disorders, their cytogenetic location, candidate genes, novel mutations identified, and advanced diagnostic tools that are currently being used for rapid detection of these abnormalities. The application of advanced technologies is rapidly changing the background of genetic research and also in clinical practice. The identification of novel disease-causing genes, mutations, and predisposing genetic variants data is getting into accelerated. The availability of huge genetic information will uphold a better indulgent of genetic disease etiology, permit early, even per-symptomatic diagnosis, and preventive measures to avoid the onset of the disease. This review will make clinicians/pediatricians to classify rare disorders with their genes responsible, leading for accurate genetic diagnosis.

Evolutionary paths to antibiotic resistance under dynamically sustained drug selection.

Antibiotic resistance can evolve through the sequential accumulation of multiple mutations. To study such gradual evolution, we developed a selection device, the 'morbidostat', that continuously monitors bacterial growth and dynamically regulates drug concentrations, such that the evolving population is constantly challenged. We analyzed the evolution of resistance in Escherichia coli under selection with single drugs, including chloramphenicol, doxycycline and trimethoprim. Over a period of ∼20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing of the evolved strains identified mutations both specific to resistance to a particular drug and shared in resistance to multiple drugs. Chloramphenicol and doxycycline resistance evolved smoothly through diverse combinations of mutations in genes involved in translation, transcription and transport. In contrast, trimethoprim resistance evolved in a stepwise manner, through mutations restricted to the gene encoding the enzyme dihydrofolate reductase (DHFR). Sequencing of DHFR over the time course of the experiment showed that parallel populations evolved similar mutations and acquired them in a similar order.

Exponential advances in Forest Genetics: the past 25 years and the next 25 weeks

Exponential advances in Forest Genetics: the past 25 years and the next 25 weeks

Suicide vectors for antibiotic marker exchange and rapid generation of multiple knockout mutants by allelic exchange in Gram-negative bacteria

Allelic exchange is frequently used in bacteria to generate knockout mutants in genes of interest, to carry out phenotypic analysis and learn about their function. Frequently, understanding of gene function in complex processes such as pathogenesis requires the generation of multiple mutant strains. In Pseudomonads and other non-Enterobacteriaceae, this is a time-consuming and laborious process based on the use of suicide vectors and allelic exchange of the appropriate mutant version of each gene, disrupted by a different antibiotic marker. This often implies the generation of a series of mutants for each gene, each disrupted by a different antibiotic marker, in order to obtain all possible double or multiple mutant combinations. In this work, we have modified this method by developing a set of 3 plasmid derivatives from the previously described suicide vector for allelic exchange, pKAS32, to make antibiotic marker exchange easier and thus accelerate the entire process. Briefly, the construction of each single gene knockout mutant is carried out by allelic exchange of the chromosomal gene with a mutant allele disrupted by the insertion of a kanamycin resistance cassette. When a double mutant strain is required, antibiotic marker exchange is performed in either one of the single mutants, using any of the three plasmid derivatives that carry the kanamycin resistance gene disrupted by either a chloramphenicol, gentamycin, or streptomycin resistance cassette. The single mutant strain, carrying now an antibiotic resistance marker other than kanamycin, can be used to introduce a second mutation using the original plasmid constructs, to generate a double mutant. The process can be repeated sequentially to generate multiple mutants. We have validated this method by generating strains carrying different combinations of mutations in genes encoding different transcriptional regulators of the Hrp type III secretion system in Pseudomonas syringae. We have also tested the genetic organisation and stability of the resulting mutant strains during growth in laboratory conditions as well as in planta.

Genomics

You have accessThe ASHA LeaderSIGnatures1 Apr 2003GenomicsLearning to Read the Instruction Manual Jill L. Elfenbein Jill L. Elfenbein Google Scholar More articles by this author https://doi.org/10.1044/leader.SIGN.08062003.26 SectionsAbout ToolsAdd to favorites ShareFacebookTwitterLinked In Just a few years ago, Time magazine declared, “Genetics—The future is now.” Population screening for gene mutations, tailoring pharmaceuticals to meet our individual needs, and gene therapy were all highlighted, not just as possibilities, but as probabilities in this new era. This spring, identification of the DNA sequence for humans—the human genome—nears completion. It is at once the end of a great task and the foundation for an even greater challenge. We have opened our instruction manual; now we must learn to read it. Over several decades, preventive medicine has decreased the contribution of infectious agents, such as rubella, to our caseloads. As a result, the percentage of individuals whose hearing-loss etiologies have a genetic component has grown. We all see patients/clients/students for whom a gene mutation, a combination of gene mutations, or the interaction of a gene mutation and environmental factors is the cause of hearing loss. In many instances, the contribution of the genetic component is, at least partially, understood; in others, we have yet to even identify the presence of a genetic component. That instruction manual will need to be on all our reading lists. If you thumb through recent issues of the New England Journal of Medicine, you will discover a new section—Genomic Medicine—edited by Alan Guttmacher and Francis Collins from the National Human Genome Research Institute of the National Institutes of Health. Genomics, they tell us, refers to the study of the functions and interactions of all the genes in our genome. Genomic Medicine contains review articles that provide an introduction to a wide variety of topics. Although the focus is not on audiology, the material is well worth the trip to the library. If it has been awhile since you have done some reading in this area, I suggest that you begin with “Genomic Medicine—A Primer” in the Nov. 7, 2002 issue and “Genetic Testing” in the Dec. 5, 2002 issue. If you are looking for information with direct application to specific disorders, then the GeneTests-GeneClinics Web site at http://www.geneclinics.org/ is a good place to visit. The editor-in-chief of this site is Roberta Pagon from the University of Washington. The site targets a wide range of health care providers and includes disease-specific review articles, lab and clinic directories, and educational materials. If hearing loss is your primary interest, then the Hereditary Hearing Loss Homepage at http://webhost.ua.ac.be/hhh/ offers you the most up-to-date information about genetics research. This site, authored by Guy Van Camp from the University of Antwerp and Richard Smith from the University of Iowa, targets researchers and clinicians with interests in hereditary hearing loss. You will find not only a listing of gene mutations and papers about them, but also a news highlights section that will direct you to recent articles, upcoming meetings, and a variety of databases. We have entered an era in which our knowledge of genetics and the genetic etiologies of communication disorders will have an expanding influence on aspects of our clinical practice ranging from taking a case history to counseling. Perhaps some day soon we will see Genomic Audiology as an ASHA Convention topic area. Author Notes Jill L. Elfenbein, is coordinator of ASHA’s Special Interest Division 7, Aural Rehabilitation and Its Instrumentation. She is an associate professor in the Department of Audiology and Speech Sciences at Michigan State University. Contact her by e-mail at [email protected]. Advertising Disclaimer | Advertise With Us Advertising Disclaimer | Advertise With Us Additional Resources FiguresSourcesRelatedDetails Volume 8Issue 6April 2003 Get Permissions Add to your Mendeley library History Published in print: Apr 1, 2003 Metrics Downloaded 130 times Topicsasha-topicsleader_do_tagleader-topicsasha-article-typesCopyright & Permissions© 2003 American Speech-Language-Hearing AssociationLoading ...

Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway

A vesicular intermediate in protein transport from the endoplasmic reticulum is detected in a subset of temperature-sensitive mutants blocked early in the yeast secretory pathway. By electron microscopy three of the mutants, sec18, sec17, and sec22, accumulate 50 nm vesicles at the nonpermissive temperature. Vesicle accumulation is blocked by the mutations sec12, sec13, sec16, and sec23 as shown by analysis of double-mutant strains. Thus the early SEC genes can be divided into vesicle forming and vesicle fusion functions. Synthetic lethal interactions between sec mutations define two groups of SEC genes, corresponding to the groups involved in vesicle formation or fusion. Mutations in two of the genes involved in vesicle fusion, SEC17 and SEC18, are lethal in combination, and five of six possible pairwise combinations of mutations in genes required for vesicle formation, SEC12, SEC13, SEC16, and SEC23, are lethal. These interactions suggest cooperation between different SEC gene products in vesicle budding and vesicle fusion processes.