TY - JOUR. T1 - Analysis of pathway mutation profiles highlights collaboration between cancer-associated superpathways. AU - Gu, Yunyan. AU - Zhao, Wenyuan. AU - Xia, Jiguang. AU - Zhang, Yuannv. AU - Wu, Ruihong. AU - Wang, Chenguang. AU - Guo, Zheng. PY - 2011/9/1. Y1 - 2011/9/1. N2 - The biological interpretation of the complexity of cancer somatic mutation profiles is a major challenge in current cancer research. It has been suggested that mutations in multiple genes that participate in different pathways are collaborative in conferring growth advantage to tumor cells. Here, we propose a powerful pathway-based approach to study the functional collaboration of gene mutations in carcinogenesis. We successfully identify many pairs of significantly comutated pathways for a large-scale somatic mutation profile of lung adenocarcinoma. We find that the coordinated pathway pairs detected by comutations are also likely to be coaltered by other molecular changes, such as alterations in multifunctional ...
AIM: We assessed the diagnostic accuracy of epidermal growth factor receptor (EGFR) mutant-specific antibodies for detecting two common activating EGFR mutations. METHODS: Immunohistochemical expression of mutation-specific antibodies against EGFR exon 19 deletion E746-A750 ((c.2235_2249del15 or c.2236_2250del15, p. Glu746_Ala750del) and exon 21 L858R point mutation (c.2573T|G, p.Leu858Arg) were assessed in a cohort of 204 resected early stage node negative lung adenocarcinomas, and protein expression was compared with DNA analysis results from mass spectrometry analysis. RESULTS: Of seven cases with L858R point mutation, six were positive by immunohistochemistry (IHC). There were three false positive cases using L858R IHC (sensitivity 85.7%, specificity 98.5%, positive predictive value 66.7%, negative predictive value 99.5%). All seven E746-A750 exon 19 deletions identified by mutation analysis were positive by IHC. Four additional cases were positive for exon 19 IHC but negative by mutation analysis.
Mitochondrial diseases, which altogether represent not so rare diseases, can be due to mutations either in the nuclear or mitochondrial genomes. Several model organisms or cell lines are usually employed to understand the mechanisms underlying diseases, yeast being one of them. However, in the case of mutations within the mitochondrial genome, yeast is a major model because it is a facultative aerobe and its mitochondrial genome can be genetically engineered and reintroduced in vivo. In this short review, I will describe how these properties can be exploited to mimic mitochondrial pathogenic mutations, as well as their limits. In particular; pathological mutations of tRNA, cytb, and ATPase genes have been successfully modeled. It is essential to stress that what has been discovered with yeast (molecular mechanisms underlying the diseases, nuclear correcting genes, import of tRNA into mitochondria or compounds from drug screening) has been successfully transferred to human patient lines, paving the way
Since Fishers (1930) development of the geometric model of the process of adaptation, it has been assumed that a mutation that affects many parts of a complex organism is less likely to be beneficial than a mutation of more restricted effect. Direct evidence supporting the generality of this supposition has been difficult to obtain, in part because of the challenge of studying high-dimensional phenotypes (Houle 2010) and because of the lack of information on the relationship between effects of pleiotropic alleles on phenotypes vs. on fitness (Paaby and Rockman 2013). By using multivariate statistical modeling of the genetic variance generated by new mutations, and of the standing genetic variance in a natural population, we have shown that selection is consistently stronger on pleiotropic mutations, supporting Fishers model of adaptation for populations in the vicinity of an adaptive optimum (Zhang 2012).. In general, we inferred strong selection acting against new mutations affecting the ...
Thesis Defense. Title: Computational Detection of Driver Mutations in Cancer Genomes. Abstract: Cancer is caused largely by the accumulation of somatic mutations during the lifetime of an individual. Recent advances in next generation sequencing (NGS) enable measurement of somatic mutations in a cohort of samples. Large-scale cancer sequencing projects like The Cancer Genome Atlas (TCGA) have generated a huge amount of somatic mutations in thousands of tumors. This thesis addresses two challenges. The first challenge is to distinguish driver mutations that are responsible for cancer development from passenger mutations, random events that do not contribute to the cancer phenotype in a cohort of samples. This is a difficult problem because most somatic mutations measured in tumor samples are passenger mutations, and only a small portion of these mutations are driver mutations. The second challenge is to accurately identify larger genomic variants, also known as structural variants (SV), one type ...
Author Summary Cancer is the consequence of an evolutionary process, which lasts several decades, is impossible to observe during most of its time, and only becomes apparent in late stages. We use mathematical modeling to shed light on the evolutionary dynamics of cancer by studying the accumulation of passenger mutations. We show that the frequencies obtained by passenger mutations depend strongly on the ratio of death and birth rates of cancer cells. We use genetic data of colorectal cancer to estimate this important quantity in vivo. We estimate the size of the cancer cell population that was present when a specific mutation first emerged. Our theory informs the analysis of cancer sequencing data and the phylogenetic reconstruction of cancer evolution.
...A specific gene mutation may be useful in predicting the level of aggr...The mutation called BRAF V600E is a genetic alteration in the BRAF o...Past studies have shown that the mutation frequently occurs in the mos...The findings come at an important time as both the incidence of thyroi...,Presence,of,gene,mutation,helps,guide,thyroid,cancer,treatment,biological,biology news articles,biology news today,latest biology news,current biology news,biology newsletters
To study the cost of chromosomal drug resistance mutations to bacteria, we investigated the fitness cost of mutations that confer resistance to different classes of antibiotics affecting bacterial protein synthesis (aminocyclitols, 2-deoxystreptamines, macrolides). We used a model system based on an in vitro competition assay with defined Mycobacterium smegmatis laboratory mutants; selected mutations were introduced by genetic techniques to address the possibility that compensatory mutations ameliorate the resistance cost. We found that the chromosomal drug resistance mutations studied often had only a small fitness cost; compensatory mutations were not involved in low-cost or no-cost resistance mutations. When drug resistance mutations found in clinical isolates were considered, selection of those mutations that have little or no fitness cost in the in vitro competition assay seems to occur. These results argue against expectations that link decreased levels of antibiotic consumption with the ...
Epidemiological evidence has long associated environmental mutagens with increased cancer risk. However, links between specific mutation-causing processes and the acquisition of individual driver mutations have remained obscure. Here we have used public cancer sequencing data to infer the independent effects of mutation and selection on driver mutation complement. First, we detect associations between a range of mutational processes, including those linked to smoking, ageing, APOBEC and DNA mismatch repair (MMR) and the presence of key driver mutations across cancer types. Second, we quantify differential selection between well-known alternative driver mutations, including differences in selection between distinct mutant residues in the same gene. These results show that while mutational processes play a large role in determining which driver mutations are present in a cancer, the role of selection frequently dominates ...
Summary: Continuous cultures of the tryptophan-requiring strain of Escherichia coli known as wp2 were continuously exposed to gamma radiation for periods of several generation times. The frequency of prototrophic revertants increased steadily during irradiation at a rate which was proportional to the radiation dose rate. The change of revertant frequency per unit dose (rad) was equal to the induced reversion rate per mutable unit. This mutation rate (ρ) was independent of population density but slightly dependent upon the presence of supplements, such as nutrient broth, to the normal minimal medium with tryptophan. There was a marked dependence of ρ upon culture temperature, the values at 16°, 22° and 37° being 1·2 × 10-11, 2·4 × 10-11 and 3·9 × 10-11 per mutable unit per rad. It is probable that only a fraction of radiation-induced changes in the genetic material which could give rise to phenotypic reversions are actually expressed, this fraction being dependent on the post-irradiation
The genetic factors underpinning the development of cancers are being discovered at an increasing pace. Cancers can have an acquired or an inherited genetic aetiology. Inherited cancer predisposition caused by a single gene mutation is normally inherited in an autosomal dominant fashion. Acquired caner at the cellular level may be caused by the loss of function of both copies of the gene acting in an autosomal recessive fashion. Gene mutations may act in different ways, some drive cell growth-oncogenes, others when the gene mutates fail to stop tumour growth - tumour suppressor genes. Other genetic mutations may cause normal DNA and cellular repair mechanisms to fail. Genetic testing may be used at the level of a tumour to inform treatment decisions or in an inherited cancer susceptibility syndrome to provide information and tailor screening and prevention strategies.
Eukaryotic cells contain numerous compartments, which have different protein constituents. Proteins are typically directed to compartments by short peptide sequences that act as targeting signals. Translocation to the proper compartment allows a protein to form the necessary interactions with its partners and take part in biological networks such as signalling and metabolic pathways. If a protein is not transported to the correct intracellular compartment either the reaction performed or information carried by the protein does not reach the proper site, causing either inactivation of central reactions or misregulation of signalling cascades, or the mislocalized active protein has harmful effects by acting in the wrong place. Numerous methods have been developed to predict protein subcellular localization with quite high accuracy. We applied bioinformatics methods to investigate the effects of known disease-related mutations on protein targeting and localization by analyzing over 22,000 missense
Complex processes such as transcription, replication, repair, and recombination require changes in chromatin structure and the interactions of numerous trans-acting factors with DNA sequences, raising the possibility that these processes may be interrelated. Here the effect of transcription on the rate of spontaneous mutation in the yeast Saccharomyces cerevisiae was examined. With the use of a lys2 frameshift allele under the control of a highly inducible promoter, the rate of spontaneous reversion was shown to increase when the mutant gene was highly transcribed. Thus, transcriptionally active DNA and enhanced spontaneous mutation rates are associated in yeast.. ...
e deficient for the mismatch repair (MMR) gene Msh2 show accelerated tumourigenesis and a reduced apoptotic response to DNA damage of methylation type. Here we examine the effect of mutation for Msh2 on in vivo mutation frequencies in the intestine as determined by loss of function at the Dolichos biflorus (Dlb-1) locus. Spontaneous mutation frequencies were scored in cohorts of ageing mice either wild type or mutant for Msh2. In mice less than 1 year old, mutation frequencies were only elevated in Msh2 null mice. However, beyond this age heterozygous Msh2 mice showed significantly higher mutation frequencies than controls. These findings implicate a gene dose dependent requirement for Msh2 in mutation suppression and prompted an analysis of young Msh2 mutants following exposure to DNA damage. Following exposure to N-methyl-N-nitro-N-nitrosoguanidine (MNNG), Msh2 deficient mice show a reduced apoptotic response and an increase in mutation frequency. Heterozygotes did not differ from controls. ...
Open-access immunosequencing data | Weber, Jeffrey | Cancer Immunology Research | Adaptive Biotechnologies | To understand prognostic factors for outcome between differentially sequenced nivolumab and ipilimumab in a randomized phase II trial, we measured T-cell infiltration and PD-L1 by immunohistochemistry, T-cell repertoire metrics, and mutational load within the tumor. We used next-generation sequencing (NGS) and assessed the association of those parameters with response and overall survival. Immunosequencing of the T-cell receptor -chain locus (TCR) from DNA of 91 pretreatment tumor samples and an additional 22 pairs of matched pre- and post treatment samples from patients who received nivolumab followed by ipilimumab (nivo/ipi), or the reverse (ipi/nivo), was performed to measure T cell clonality and fraction. Mutational and neoantigen load were also assessed by NGS in 82 of the 91 patients. Tumors were stained using immunohistochemistry for PD-L1+ and CD8+ T cells. Pretreatment tumor TCR
A gene mutation may accelerate the loss of memory and thinking skills in people who are at risk for Alzheimers disease, according to a study published in the May 3, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology.
THE number of compensatory mutations that will affect a specific deleterious mutation is a fundamental evolutionary quantity of which little is known. A mutation is compensatory if it has a beneficial effect on fitness that is conditional on the presence of a deleterious mutation at a different site in the genome (Kimura 1985). Hence, a compensatory effect is the outcome of a strong epistatic interaction between two mutations. Each compensatory mutation represents an alternate genetic solution to adaptation; thus, fitness recovery from the accumulation of deleterious mutations becomes less likely to occur by back mutation when compensatory mutations are increasingly common (Whitlock and Otto 1999). Indeed, one must invoke a compensatory mutation to explain the rapid, stepwise recovery of fitness observed in mutationally degraded experimental populations (Burch and Chao 1999; Moore et al. 2000; Estes and Lynch 2003). Compensatory mutations are also implicated in the persistence of alleles that ...
When populations of microorganisms are exposed to nonlethal selections, mutations that relieve the selective pressure arise (7), a phenomenon called adaptive mutation (6). Although it originally seemed that only useful mutations appeared (7), it is now clear that selected mutations are accompanied by nonselected mutations, i.e., the process is not directed to useful genes (12).. Most research on adaptive mutation has focused on a strain of Escherichia coli, called FC40, that cannot utilize lactose (Lac−) but that readily reverts to lactose utilization (Lac+) when lactose is its only carbon source (6). The process that produces adaptive Lac+ mutations is not the same as that which produces Lac+ mutations during normal growth. Unlike growth-dependent mutations, almost all adaptive Lac+ mutations are dependent on recombination functions (6, 10, 24). While several different types of sequence changes revert the Lac− allele during growth, adaptive Lac+ mutations are almost all −1-bp frameshifts ...
A fundamental task in precision oncology is to perform mutation profiling of tumors, which traditionally requires invasive tumor biopsy. Liquid biopsy, which requires a simple blood draw, provides a surrogate option for tumor biopsy. Liquid biopsy is noninvasive, repeatable, and especially useful when a tumors location makes tissue biopsy unfeasible.. However, the mutation profiling of cell-free DNA (cfDNA) is challenging, as conventional mutation callers are primarily designed for the mutation calling of genomic DNA. Unlike tumor biopsy, cfDNA is a mixture of DNA derived from tumors and that from normal cells, where tumor-derived cfDNA accounts for a minor fraction. As a result, mutations from tumors have weak signals in blood samples and are therefore hard to identify using conventional methods.. To address this challenge, in our recent work published in Nature Communications [1], we present cfSNV, a cfDNA somatic single nucleotide variant (SNV) caller with five innovative techniques to ...
Population included 59% of adenocarcinoma, 37% of women and 19% of non-smokers. Overall mutation rate is 46%: 31 EGFR mutations (13%) and 78 KRAS mutations (33%); 40 new mutations compared to previous study were found: 9 EGFR and 31 KRAS. In the ERMETIC 2 cohort, OS and PFS remained significantly (global test p < 0.01) better for EGFR mutated (hazard ration [HR] 0.57 [95%CI: 0.33-1.00] and 0.47 [0.28-0.78] respectively) and worse for KRAS mutated (HR 1.35 [0.97-1.88] and 1.16 respectively [0.85-1.59]) compared to wild-type (WT) NSCLC. No prognostic significant difference was found in the 177 pts common to both cohorts between pts with KRAS mutation in both cohorts (n= 28) and those with new (n = 31) mutations. In the 228 pts with several techniques, KRAS mutations detected by less sensitive technique (n = 42) have a lower OS compared to WT than those detected only by the best sensitive technique (n = 34), but are not significantly different: 1.63 (1.09-2.44) and 1.08 (0.69-1.69); results between ...
Hollander, W F., Hydrocephalic-polydactyl, a recessive pleiotropic mutant in the mouse and its location in chromosome 6. (1976). Subject Strain Bibliography 1976. 3055 ...
A mutation in a single gene can cause endometrial cancer that is responsive to a specific drug therapy, researchers at UT Southwestern Medical Center have found in an animal study.
3799 Genomic instability involves the accumulation of mutations and is a hallmark of neoplastic development in gastrointestinal malignancies such as colorectal carcinoma. Mutations in specific cancer genes contribute to the malignant phenotype for colorectal carcinoma. For example, mutations in APC, KRAS and TP53 are critical to the development of colorectal cancer. Mutations in genes like EGFR influence the response of molecular-targeted therapies. Undoubtedly, there are other critical gene mutations to be discovered and comprehensive mutation discovery from individual cancer genomes will increase our understanding of the genetics underlying any individual tumors phenotype. This mutation profile may provide prognostic and predictive genetic biomarkers. However, current technologies are severely limited in screening large numbers of genes for mutations. As a solution, we describe the development and application of a novel resequencing strategy for point mutation discovery on a massively ...
A mutation is any change occurring in the message that a gene carries. Mutations mainly arise as copy errors when DNA is replicated at mitosis and meiosis. Darwinian evolution requires a constant supply of variation: much of it is supplied by mutation, and a mutation-selection balance can maintain a genetic polymorphism. The first major geneticist to study mutation was H.J. Muller, who demonstrated it can be induced by X-rays. He also recognized that the rate of mutation in nature is extremely low, and that they are almost always deleterious to the fitness of the organism. The accumulation of deleterious mutations places a mutational load on the population. Mutations can occur at single base level or at chromosomal level. The effects of mutation can occasionally be very dramatic: some of these fruitflies have suffered mutations which alter the number of wings that develop... Is mutation directed?. ...
Rare mutations in the switch III region of Ras can increase its nanoscale clustering, which enhances effector recruitment and downstream signaling.
|p>p53 is a tumor suppressor protein encoded by the TP53 gene that responds to DNA damage by regulating cell-cycle arrest, apoptosis and senescence. These p53 Hotspot Mutation Cell Panels are composed of select cell lines derived from tumors of various tissue origins. The p53 mutational status of these lines have been sequenced and validated by ATCC.|/p>
|p>p53 is a tumor suppressor protein encoded by the TP53 gene that responds to DNA damage by regulating cell-cycle arrest, apoptosis and senescence. These p53 Hotspot Mutation Cell Panels are composed of select cell lines derived from tumors of various tissue origins. The p53 mutational status of these lines have been sequenced and validated by ATCC.|/p>
Researchers assigned levels of risk to 25 mutations associated with breast and ovarian cancer in a large, Stanford-led study. The results may be helpful in guiding treatment and screening recommendations.
Listing of all Polbase results with context for Reference: Amino acid changes coded by bacteriophage T4 DNA polymerase mutator mutants. Relating structure to function., Polymerase: T4 G298D, Property: Nucleotide Substitution Rate
Deletion of the I265-F268 and T271-K277 regions in the large lumenally exposed loop of the CP47 protein are known to lead to a loss of photoautotrophic growth. Here, these regions have been investigated by combinatorial mutagenesis and pseudorevertant mapping. No single amino-acid residue in the I265-F268 region was found to be critical for function, but a large hydrophobic residue at position 267 and preferentially an aromatic residue at position 268 appeared to be required for photoautotrophic growth. Starting from an obligate photoheterotrophic mutant lacking the T271-K277 region, photoautotrophic pseudorevertants were generated with short in-frame tandem repeats near the site of the original deletion, partially or fully restoring the length of the original protein. These pseudorevertants were sensitive to oxygen indicating that the T271-K277 region may provide PS II stability and/or protection against oxygen-dependent photoinactivation. Pseudorevertants with much improved photoautotrophic ...
Researchers assigned levels of risk to 25 mutations associated with breast and ovarian cancer in a large, Stanford-led study. The results may be helpful in guiding treatment and screening recommendations.
Researchers assigned levels of risk to 25 mutations associated with breast and ovarian cancer in a large, Stanford-led study. The results may be helpful in guiding treatment and screening recommendations.
Using real-time PCR to detect HIV resistance mutations present at low levels, Jeffrey Johnson and colleagues investigate prevalence and clinical implications of minority transmitted mutations.
BioMotiv, a drug development accelerator associated with The Harrington Project, and Rutgers, the State University of New Jersey, are announcing the formation of a new biotechnology startup, Z53 Therapeutics. Z53 Therapeutics aims to develop novel anti-cancer drugs that target tumors with p53 mutations.
Most truncation or deletion mutations underlying HI are thought to lead to severe loss of ABCA12 protein function affecting important nucleotide-binding fold domains and/or transmembrane domains. Thus far, in HI patients, at least one mutation on each allele must be a truncation or deletion mutation within a conserved region to cause serious loss of ABCA12. Complete loss of ABCA12 function due to homozygous or compound heterozygous truncation mutations always results in the HI patient phenotype. ...
Scientists make a DNA breakthrough by using multi-gene test to predict the risk of five diseases.. The key to prevention is identifying people who are at higher risk for diseases early on. Since most common diseases have a genetic component, we could start classifying people based on their genetic risk.. This is where genetic variants come into play. Genetic variants are small changes in DNA that exist between people, which can contribute to disease risk. However, most common diseases of today like heart disease and diabetes, are influenced by more than one gene.. Individually each gene only makes a small contribution towards disease risk. But when found together, they play a significant role in a persons genetic predisposition to disease. Unfortunately predicting disease risk based on multiple genes isnt an easy task.. However, according to ground breaking research published in the journal of Nature Genetics, this is no longer the case. Scientist can now effectively predict the risk of ...
The causes underlying racial disparities in cancer are multifactorial. In addition to socioeconomic issues, biological factors may contribute to these inequities, especially in disease incidence and patient survival. To date, there have been few studies that relate the disparities in these aspects to genetic aberrations. In this work, we studied the impacts of race on the patient survival and tumor mutation burden using the data released by the Cancer Genome Atlas (TCGA). The potential relationship between mutation burden and disease incidence is further inferred by an integrative analysis of TCGA data and the data from the Surveillance, Epidemiology, and End Results (SEER) Program. The results show that disparities are present (p | 0.05) in patient survival of five cancers, such as head and neck squamous cell carcinoma. The numbers of tumor driver mutations are differentiated (p | 0.05) over the racial groups in five cancers, such as lung adenocarcinoma. By treating a specific cancer type and a racial
Genetically modified mice are an essential tool for modeling disease-causing mechanisms and discovering gene function. SNP genotyping was traditionally used to associate candidate regions with traits in the mouse, but failed to reveal novel variants without further targeted sequencing. Using a robust set of computational protocols, we present a platform to enable scientists to detect variants arising from whole-genome and exome sequencing experiments. This article guides researchers on aligning reads to the mouse genome, quality-assurance strategies, mutation discovery, comparing mutations to previously discovered mouse SNPs, and the annotation of novel variants, in order to predict mutation consequences on the protein level. Challenges unique to the mouse are discussed, and two protocols use self-contained containers to maintain version control and allow users to adapt our approach to new techniques by upgrading container versions. Our protocols are suited for servers or office workstations and ...
Vorkas, P.A.; Poumpouridou, N.; Agelaki, S.; Kroupis, C.; Georgoulias, V.; Lianidou, E.S., 2010: PIK3CA hotspot mutation scanning by a novel and highly sensitive high-resolution small amplicon melting analysis method
This report describes mutants of the zebrafish having phenotypes causing a general arrest in early morphogenesis. These mutants identify a group of loci making up about 20% of the loci identified by mutants with visible morphological phenotypes within the first day of development. There are 12 Class I mutants, which fall into 5 complementation groups and have cells that lyse before morphological defects are observed. Mutants at three loci, speed bump, ogre and zombie, display abnormal nuclei. The 8 Class II mutants, which fall into 6 complementation groups, arrest development before cell lysis is observed. These mutants seemingly stop development in the late segmentation stages, and maintain a body shape similar to a 20 hour embryo. Mutations in speed bump, ogre, zombie, specter, poltergeist and troll were tested for cell lethality by transplanting mutant cells into wild-type hosts. With poltergeist, transplanted mutant cells all survive. The remainder of the mutants tested were autonomously but ...
Genetic mutations have two major types: large mutation (deletion, insertion, duplication, and inversion) and point mutation (nonsense, missense, and frame shift). Some mutations can induce DNA transcription and translation errors eventually causing protein dysfunction that leads to disease [1, 2]. Currently, many whole genome scale association studies between disease and variation are being published [3]. However, medical researchers have had to go through mutations in patient DNA to detect mutations that may be the cause of a disease [4, 5].. There are many human disease gene databases that contain disease-causing mutation information as locus-specific databases (LSDBs). Also, large databases, such as Online Mendelian Inheritance in Man (OMIM) [6] and the Human Gene Mutation Database (HGMD) [7], collect and describe comprehensively all disease-related genes. In contrast, LSDBs usually describe variations in a small number of genes. The LSDBs aim to provide particular genetic mutation ...
Seven single gene mutations are known to cause hypertension; this article guides clinicians through identification of the relatively uncommon defects, associated laboratory findings, and treatments.
The transcription factor CCAAT-enhancer-binding protein alpha (C/EBPα) is a master regulator of granulopoiesis and regulates the switch between proliferating, uncommitted progenitors and cell-cycle-arrested, differentiated myeloid cells. Usage of two alternative translation initiation sites in the CEBPA mRNA results in expression of a full-length C/EBPα protein p42 (42 kDa) and a shorter p30 isoform (30 kDa). CEBPA mutations are found in 9-15% of Acute Myeloid Leukemia (AML) patients. N-terminal frameshift mutations in the CEBPA gene lead to selective ablation of p42 expression, while C-terminal mutations disrupt the dimerization and DNA-binding ability of C/EBPα. AML patients harbor either mono- or biallelic CEBPA mutations (CEBPAmo or CEBPAbi) and both genotypes are frequently associated with concurrent mutations in other genes. The most commonly co-occurring mutations in both groups are loss-of-function mutations in the methylcytosine dioxygenase TET2 (44.4% in CEBPAmo / 34.8% in CEBPAbi). ...
From Jules: there was quite a bit of discussion at the workshop this year about using sensitive testing to identify low-level or minority genotypic resistance. At last years Resistance Workshop the CDC and Mike Kozal from Yale reported in oral presentations that minority mutations can lead to viral failure. Concerns are how to translate these potential concerns into the clinic. There are some lingering concerns among a few that further confirmation is required before presuming that the presence of low-level mutations is a reliable test for not using a drug, despite several studies reporting that the risk for viral failure significantly increases if these mutations are present; but not everyone fails if minority mutations are present, so are you throwing out a good drug by avoiding it? Still the studies so far presented find there is a significantly increased risk of viral failure. Tests to screen for minority mutations are not clinically available yest, as far as I know. But there were several ...
Ovarian and breast cancer can be either sporadic or hereditary. Sporadic cancers make up the vast majority (85-90%) of ovarian and breast cancers and are not associated with family history of either cancer or inherited cancer-associated mutations. Sporadic cancers arise from genetic mutations acquired in some cells of the body by events part of normal metabolism and environmental factors. This type of cancer can happen to anyone. Most acquired gene mutations are not shared among relatives or passed on to children.. Hereditary (also known as inherited, or familial) cancers are those that occur due to genetic mutations that are inherited from mom or dad. Other blood relatives may also share these same gene mutations. Parents give one copy of each gene to their children. If a parent has a genetic mutation in a gene, each of their children have a 50% chance of inheriting that mutation. Therefore, even in families with hereditary cancer, not all family members inherit the mutation that is causing ...
Mutation assays can then be grouped together into PCR arrays based off common themes to enable users to profile a focused set of mutations. The mutations on an array are selected based on a commonality, such as being from the same gene, signaling pathway, or cancer type. For example, users could profile the most common 84 mutations in breast cancer or the 44 most common mutations in APC. The Custom qBiomarker Somatic Mutation PCR Arrays allow users to select the mutations that they wish to profile. Together, the qBiomarker Somatic Mutation products facilitate sensitive detection and profiling of mutations in cancer cells or tumor samples ...
Purpose: : To identify and characterize the gene mutation responsible for photoreceptor degeneration in the rd3 mouse. Methods: : We screened genes in the known rd3 (RBF/DnJ) mapped region by direct sequencing. We additionally screened other rd3 lines (RBJ/Dn, STOCK Rb(11.13)4Bnr/J and STOCK In(5)30Rk) and normal mouse strains to verify the alteration. We carried out a mutation screen of the human RD3 gene in patients with retinopathies and examined 431 patients of Caucasian ethnicity and 103 of Asian-Indian ancestry. Amino acid changes that were identified in patients but not in controls are being examined by immunoblot analysis and immunocytochemisty to determine their effect(s) on protein stability or localization. Results: : The rd3 mutation is a homozygous C to T transition, leading to a stop codon, which is predicted to result in a premature truncation of the rd3 protein. The mutation was present in all rd3 lines tested (RBF/DnJ, RBJ/Dn, 4bnr and IN-30) but not in the control lines ...
Comprehensive mutational profiling data now available on all major cancers have led to proposals of novel molecular tumor classifications that modify or replace the established organ- and tissue-based tumor typing. The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology. The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates. Here, we present a computational approach that facilitates the systematic analysis of the histological context dependency of mutational effects by integrating genomic and proteomic tumor profiles across cancers. To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance)
Dna Mutation Practice Worksheet Answers Luxury Mutations Ws Answer Key Mutations Worksheet Name Lg Date one of Chessmuseum Template Library - free resume template for word education on a resume example ideas, to explore this Dna Mutation Practice Worksheet Answers Luxury Mutations Ws Answer Key Mutations Worksheet Name Lg Date idea you can browse by and . We hope your happy with this Dna Mutation Practice Worksheet Answers Luxury Mutations Ws Answer Key Mutations Worksheet Name Lg Date idea. You can download and please share this Dna Mutation Practice Worksheet Answers Luxury Mutations Ws Answer Key Mutations Worksheet Name Lg Date ideas to your friends and family via your social media account. Back to 50 Dna Mutation Practice Worksheet Answers. ...
TY - JOUR. T1 - Modeling post-translational modifications and cancer-associated mutations that impact the heterochromatin protein 1α-importin α heterodimers. AU - Zimmermann, Michael T.. AU - Williams, Monique M.. AU - Klee, Eric W. AU - Lomberk, Gwen A.. AU - Urrutia, Raul. PY - 2019/1/1. Y1 - 2019/1/1. N2 - Heterochromatin protein 1α (HP1α) is a protein that mediates cancer-associated processes in the cell nucleus. Proteomic experiments, reported here, demonstrate that HP1α complexes with importin α (IMPα), a protein necessary for its nuclear transport. This data is congruent with Simple Linear Motif (SLiM) analyses that identify an IMPα-binding motif within the linker that joins the two globular domains of this protein. Using molecular modeling and dynamics simulations, we develop a model of the IMPα-HP1α complex and investigate the impact of phosphorylation and genomic variants on their interaction. We demonstrate that phosphorylation of the HP1α linker likely regulates its ...
As climate change and population growth threaten to destabilize global food security, plant breeders are ramping up efforts to create better, more productive crops. But in order to introduce new traits, breeding techniques typically rely on rare genetic recombination events during meiosis.. Now, a study published in Nature Plants demonstrates that inactivating a single gene called RECQ4 can triple the number of recombination events during meiosis in a variety of distantly-related crop species, including rice (Oryza sativa), pea (Pisum sativum), and tomato (Solanum lycopersicum).. Such meiotic manipulation has been demonstrated before, but not in crop species. These mutations were around in Arabidopsis for several years. And then suddenly to see that this all works in crops. Thats fantastic, says Erik Wijnker, a plant biotechnologist at Wageningen University and Research in the Netherlands who was not involved in the study.. During meiosis, parental chromosomes move close enough to partially ...
All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry driver mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate
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The dominant paradigm for the evolution of mutator alleles in bacterial populations is that they spread by indirect selection for linked beneficial mutations when bacteria are poorly adapted. the first experimental evidence that direct selection can favour mutator alleles in bacterial populations, and pave the way for BEZ235 manufacturer future studies to understand how mutation and DNA repair are linked to stress responses and how this affects the evolution of bacterial mutation rates. mutant displays altered expression of a small number of housekeeping genes [16], raising the possibility that direct fitness costs and benefits may be associated with mutator alleles as a result of the pleiotropic effects of mutator alleles on gene expression. While the initial goal of this study was to investigate the interplay between BEZ235 manufacturer phenotypic and genetic changes in mutation rates in response to stress, preliminary findings led us to study the impact of direct stress-imposed selection on ...
Ilie, MI.; Lassalle, S.; Long-Mira, E.; Bonnetaud, C.; Bordone, O.; Lespinet, V.; Lamy, A.; Sabourin, JC. et al. (May 2014). Diagnostic value of immunohistochemistry for the detection of the BRAF(V600E) mutation in papillary thyroid carcinoma: comparative analysis with three DNA-based assays.. Thyroid 24 (5): 858-66. doi:10.1089/thy.2013.0302. PMID 24417277. ...
NSCLC-associated EGFR mutations are most frequently heterozygous. However, Paez et al. (18) reported one mutation involving exon 19 that appeared to be homozygous, and we detected two such cases. Interpretation of mutational status solely from DNA sequencing can be problematic. On the one hand, contaminating normal cells with wild-type EGFR could account for apparent heterozygosity; on the other hand, amplification of mutant EGFR, as occurs in lung cancer (23), could account for detection of only mutant sequences. Mouse models expressing mutant EGFR proteins in the lung and analysis of mutant-positive NSCLCs by fluorescence in situ hybridization and/or array-based comparative genomic hybridization may help address these issues. Interestingly, in one of these tumors (G3), we detected a heterozygous intronic polymorphism downstream of exon 19 (data not shown). In this case, it is probable that a gene conversion event occurred, encompassing the area of deletion in exon 19.. Five of 17 reported ...
Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase (rpoB) across eight strains that span the diversity of the genus Pseudomonas We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional
TY - JOUR. T1 - Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. AU - Totoki, Yasushi. AU - Tatsuno, Kenji. AU - Covington, Kyle R.. AU - Ueda, Hiroki. AU - Creighton, Chad J.. AU - Kato, Mamoru. AU - Tsuji, Shingo. AU - Donehower, Lawrence A.. AU - Slagle, Betty L.. AU - Nakamura, Hiromi. AU - Yamamoto, Shogo. AU - Shinbrot, Eve. AU - Hama, Natsuko. AU - Lehmkuhl, Megan. AU - Hosoda, Fumie. AU - Arai, Yasuhito. AU - Walker, Kim. AU - Dahdouli, Mahmoud. AU - Gotoh, Kengo. AU - Nagae, Genta. AU - Gingras, Marie Claude. AU - Muzny, Donna M.. AU - Ojima, Hidenori. AU - Shimada, Kazuaki. AU - Midorikawa, Yutaka. AU - Goss, John A.. AU - Cotton, Ronald. AU - Hayashi, Akimasa. AU - Shibahara, Junji. AU - Ishikawa, Shumpei. AU - Guiteau, Jacfranz. AU - Tanaka, Mariko. AU - Urushidate, Tomoko. AU - Ohashi, Shoko. AU - Okada, Naoko. AU - Doddapaneni, Harsha. AU - Wang, Min. AU - Zhu, Yiming. AU - Dinh, Huyen. AU - Okusaka, Takuji. AU - Kokudo, Norihiro. AU - Kosuge, Tomoo. AU - ...
TY - JOUR. T1 - The mutational landscape of adenoid cystic carcinoma. AU - Ho, A.S.. AU - Kannan, K.. AU - Roy, D.M.. AU - Morris, L.G.T.. AU - Ganly, I.. AU - Katabi, N.. AU - Ramaswami, D.. AU - Walsh, L.A.. AU - Eng, S.. AU - Huse, J.T.. AU - Zhang, J.N.. AU - Dolgalev, I.. AU - Huberman, K.. AU - Heguy, A.. AU - Viale, A.. AU - Drobnjak, M.. AU - Leversha, M.A.. AU - Rice, C.E.. AU - Singh, B.. AU - Iyer, N.G.. AU - Leemans, C.R.. AU - Bloemena, E.. AU - Ferris, R.L.. AU - Seethala, R.R.. AU - Gross, B.E.. AU - Liang, Y.P.. AU - Sinha, R.. AU - Peng, L.K.. AU - Raphael, B.J.. AU - Turcan, S.. AU - Gong, Y.X.. AU - Schultz, N.. AU - Kim, S.. AU - Chiosea, S.. AU - Shah, JP. AU - Sander, C. AU - Lee, W.. AU - Chan, T.A.. PY - 2013. Y1 - 2013. U2 - 10.1038/ng.2643. DO - 10.1038/ng.2643. M3 - Article. VL - 45. SP - 791. EP - 798. JO - Nature Genetics. JF - Nature Genetics. SN - 1061-4036. IS - 7. ER - ...
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C | T and A | G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational
A research team, headed by Theodore Friedmann, MD, professor of pediatrics at the University of California, San Diego School of Medicine, says a gene mutation that causes a rare but devastating neurological disorder known as Lesch-Nyhan syndrome appears to offer clues to the developmental and neuronal defects found in other, diverse neurological disorders like Alzheimers, Parkinsons and Huntingtons diseases. The findings, published in the October 9, 2013 issue of the journal PLOS ONE, provide the first experimental picture of how gene expression errors impair the ability of stem cells to produce normal neurons, resulting instead in neurological disease. More broadly, they indicate that at least some distinctly different neurodevelopmental and neurodegenerative disorders share basic, causative defects. The scientists say that understanding defects in Lesch-Nyhan could help identify errant processes in other, more common neurological disorders, perhaps pointing the way to new kinds of ...
The morphological features of tumors are closely related to their growth patterns [8]. Polypoid tumors are believed to exhibit a predominantly vertical growth pattern, rather than a horizontal growth pattern, while non-polypoid tumors are believed to exhibit the opposite pattern, resulting in horizontal growth. Although there are some reports that LSTs have distinct biological characteristics compared to polypoid tumors [9, 10], the mechanism by which the LST conformation is generated remains unknown.. LSTs are believed to have distinct characteristics in terms of histological and genetic features [11]. Several molecular characteristics of LSTs have been described, including alteration of the adenomatous polyposis coli (APC) gene or β-catenin [12-14] affecting the WNT/APC/β-catenin signaling pathway, mutation of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) [12, 15-20]. However, the molecular background of LSTs has remained largely unknown [19, 21]. Most of these studies have ...
Somatic genetic mutation in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene has been linked to poor prognosis and resistance to various targeted therapeutics in Non Small Cell Lung Cancer (NSCLC). Therapeutic strategies that target tumors harboring these mutations represent an unmet medical need. In this study, we investigated the relationship between antifolate sensitivity and KRAS mutation/amplification status in NSCLC.. Human NSCLC cell lines (KRAS wild type, KRAS mutant non-amplified and KRAS mutant amplified) were treated with Methotrexate (MTX) or Pemetrexed (PEM) and assayed for proliferation after 72h. In these studies, 5 out of 7 KRASwt (wildtype) cells and all KRASmut (mutant) amplified cells showed resistance to MTX treatment (IC50 ,10μM). In contrast, growth of all KRASmut non-amplified cell lines studied was inhibited with MTX treatment (IC50 ,100nM). Similar effects were observed for PEM in this study. Interrogation of the NCI Developmental Therapeutics ...
This charge from a basic to an uncharged amino acid is probably consistent with disease and the mutation occurs at a CG dinucleotide, a known mutation hot spot. This mutation was detected in 2 sibs with CF and is associated with an X2 K1 haplotype, the other mutation in this family is also on a X2 K1 haplotype and is undefined. In the original report, R297Q was not detected in a further 54 CF chromosomes with an unidefined mutations and 50 normal chromosomes, all samples were of Northern Irish origin. Dubourg argued that R297Q is a rare polymorphism rather than a deleterious mutation as usually reported. The first supportive evidence came from a family where R297Q was associated with two of the most severe molecular defects DF508 or N1303K on healthy subjects (DORVAL, JEZEQUEL, CHAUVEL, DUBOURG et al. (1995) Human Mutation, 6 : 334-335). More recently, Dubourg et al. identified the same aminoacid change (R297Q) in association with the 574delA mutation in an healthy subject. (Christèle DUBOURG, ...
To date, approximately 70%-80% of XLRP cases are found to carry mutations in RPGR and up to 20% are found to carry mutations in RP2 [10]. The exon ORF15, which contains a purine-rich domain of an approximately 1706-bp coding sequence and is predicted to encode a repetitive glycine and glutamate region at the C-terminus of the protein, is a mutation hot spot for XLRP [12]. Between 30% and 80% of RPGR mutations are identified in exon ORF15, followed by mutation frequencies that are similar for RP2 and RPGR exons 1-15 [11-13,24-28]. No mutation has yet been identified in exons 16-19. Based on these results and to keep costs low, Neidhardt and coworkers proposed a screening strategy for routine molecular genetics testing of XLRP cases by direct sequencing and recommended beginning with the screening of an XLRP male patient by ORF15 mutation analysis [14]. After identification of an ORF15 mutation, the molecular diagnosis is considered confirmed since patients with an additional mutation in exons 1 ...
Looking for natural mutation? Find out information about natural mutation. A mutation that occurs spontaneously, that is, in an individual not specifically exposed to a known mutagen Explanation of natural mutation
Methods We designed a high-throughput sequencing panel to identify variants in 15 genes (7 known SVD genes, 8 SVD-related disorder genes). The panel was used to screen a population of 950 patients with younger-onset (≤70 years) MRI-confirmed SVD stroke, recruited from stroke centers across the United Kingdom. Variants were filtered according to their frequency in control databases, predicted effect, presence in curated variant lists, and combined annotation dependent depletion scores. Whole genome sequencing and genotyping were performed on a subset of patients to provide a direct comparison of techniques. The frequency of known disease-causing and pertinent variants of uncertain significance was calculated. ...
When the DNA polymerase that replicates the Escherichia coli chromosome, DNA polymerase III, makes an error, there are two primary defenses against mutation: proofreading by the ϵ subunit of the holoenzyme and mismatch repair. In proofreading-deficient strains, mismatch repair is partially saturated and the cells response to DNA damage, the SOS response, may be partially induced. To investigate the nature of replication errors, we used mutation accumulation experiments and whole-genome sequencing to determine mutation rates and mutational spectra across the entire chromosome of strains deficient in proofreading, mismatch repair, and the SOS response. We report that a proofreading-deficient strain has a mutation rate 4000-fold greater than wild-type strains. While the SOS response may be induced in these cells, it does not contribute to the mutational load. Inactivating mismatch repair in a proofreading-deficient strain increases the mutation rate another 1.5-fold. DNA polymerase has a bias for
The qBiomarker Somatic Mutation PCR Assays are a fast and reliable mutation analysis tool using ARMS® (Amplification Refractory Mutation System) primer-based allele discrimination and Hydrolysis Probe-based quantitative real-time PCR technology. It utilizes a proprietary and experimentally verified algorithm for designing mutation-specific qPCR primers and probe. Each qBiomarker Somatic Mutation PCR Assay is subjected to rigorous experimental verification. Both sensitive detection of the intended mutation in a sample (as low as 1% mutant sample on a wild-type sample background) and assay specificity (i.e. discrimination between mutant sample and wild-type sample) are guaranteed when used with the qBiomarker Probe Master Mix. A gene-specific reference assay for checking sample quality and measuring sample input and gene copy dosage is included for each mutation assay. See the qBiomarker Somatic Mutation PCR Array System User Manual/ Handbook for protocol to follow.. The qBiomarker Somatic ...
The qBiomarker Somatic Mutation PCR Assays are a fast and reliable mutation analysis tool using ARMS® (Amplification Refractory Mutation System) primer-based allele discrimination and Hydrolysis Probe-based quantitative real-time PCR technology. It utilizes a proprietary and experimentally verified algorithm for designing mutation-specific qPCR primers and probe. Each qBiomarker Somatic Mutation PCR Assay is subjected to rigorous experimental verification. Both sensitive detection of the intended mutation in a sample (as low as 1% mutant sample on a wild-type sample background) and assay specificity (i.e. discrimination between mutant sample and wild-type sample) are guaranteed when used with the qBiomarker Probe Master Mix. A gene-specific reference assay for checking sample quality and measuring sample input and gene copy dosage is included for each mutation assay. See the qBiomarker Somatic Mutation PCR Array System User Manual/ Handbook for protocol to follow.. The qBiomarker Somatic ...
Design To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included. ...
QUESTION: There is a genetic component to Alzheimers. Yet, genetic markers for Alzheimers have yet to be identified. What makes Alzheimers so complex that it is extremely difficult to find genetic and biomarkers and treatment for the disease?. ANSWER: AD is most likely due to a combination of genetic susceptibility and environmental influence. Early-onset AD is a rare form of AD, affecting only about 5 percent of all people who have AD. It develops in people ages 30 to 60.. Some cases of early-onset AD, called familial AD (FAD), are inherited. FAD is caused by a number of different gene mutations on chromosomes 21, 14, and 1, and each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.. Even if only one of these mutated genes is inherited from a parent, the person ...
Activating mutations in the PIK3CA gene have been identified in a variety of human malignancies and are commonly detected in hotspot codons located in the helical and kinase domains in exons 9 and 20. Existing methodologies for the detection of PIK3CA mutations are time-consuming and/or expensive. In the present study we describe the first application of a PIK3CA SNaPshot assay to the screening of frequent mutations in these exons. A SNaPshot assay for the simultaneous detection of four frequent PIK3CA hotspot mutations (E542K, E545G, E545K and H1047R) has been developed and evaluated. The assay combines multiplex PCR amplification with a multiplex primer extension assay to allow targeted detection of all four mutations in one reaction. The method was tested using samples that had previously been analysed for mutations by high-resolution melting analysis and sequencing. All mutations detected were concordant and no false positive results were obtained. Sensitivity tests showed that the SNaPshot assay
Primary pulmonary enteric adenocarcinoma (PEAC) is an extremely rare variant of invasive lung cancer. It is highly heterogeneous while shares some common morphologic and immunohistochemical features with usual pulmonary adenocarcinoma (PAC) and colorectal adenocarcinoma (CRAC), making the differential diagnosis difficult. At present there are only limited studies about distinctive features of primary PEAC and the results are often inconsistent. We retrospectively analyzed total 129 primary PEACs and 50 CRACs that were published since 1991 or diagnosed in our centre. Among them eight typical samples of primary PEACs and usual PACs were detected by targeted exome sequencing. The combination of CK7+/CDX2+ acquires high sensitivity (71.3%) and specificity (82%) in differential diagnosis of PEACs from CRAC. The primary PEACs harbor a high incidence of KRAS mutation but almost absent of EGFR mutation. Moreover, compared with usual PACs, the primary PEACs have higher nonsynonymous tumor mutation burden and
Primary pulmonary enteric adenocarcinoma (PEAC) is an extremely rare variant of invasive lung cancer. It is highly heterogeneous while shares some common morphologic and immunohistochemical features with usual pulmonary adenocarcinoma (PAC) and colorectal adenocarcinoma (CRAC), making the differential diagnosis difficult. At present there are only limited studies about distinctive features of primary PEAC and the results are often inconsistent. We retrospectively analyzed total 129 primary PEACs and 50 CRACs that were published since 1991 or diagnosed in our centre. Among them eight typical samples of primary PEACs and usual PACs were detected by targeted exome sequencing. The combination of CK7+/CDX2+ acquires high sensitivity (71.3%) and specificity (82%) in differential diagnosis of PEACs from CRAC. The primary PEACs harbor a high incidence of KRAS mutation but almost absent of EGFR mutation. Moreover, compared with usual PACs, the primary PEACs have higher nonsynonymous tumor mutation burden and
Somatic mutations in epigenetic enzymes are frequently found in cancer tissues. The MLL3 H3K4-specific protein lysine monomethyltransferase is an important epigenetic enzyme, and it is among the most recurrently mutated enzymes in cancers. MLL3 mainly introduces H3K4me1 at enhancers. We investigated the enzymatic properties of MLL3 variants that carry somatic cancer mutations. Asn4848 is located at the cofactor binding sites, and the N4848S exchange renders the enzyme inactive. Tyr4884 is part of an aromatic pocket at the active center of the enzyme, and Y4884C converts MLL3 from a monomethyltransferase with substrate preference for H3K4me0 to a trimethyltransferase with H3K4me1 as preferred substrate. Expression of Y4884C leads to aberrant H3K4me3 formation in cells. Our data show that different somatic cancer mutations of MLL3 affect the enzyme activity in distinct and opposing manner highlighting the importance of experimentally studying the effects of somatic cancer mutations in key regulatory
Somatic mutations in epigenetic enzymes are frequently found in cancer tissues. The MLL3 H3K4-specific protein lysine monomethyltransferase is an important epigenetic enzyme, and it is among the most recurrently mutated enzymes in cancers. MLL3 mainly introduces H3K4me1 at enhancers. We investigated the enzymatic properties of MLL3 variants that carry somatic cancer mutations. Asn4848 is located at the cofactor binding sites, and the N4848S exchange renders the enzyme inactive. Tyr4884 is part of an aromatic pocket at the active center of the enzyme, and Y4884C converts MLL3 from a monomethyltransferase with substrate preference for H3K4me0 to a trimethyltransferase with H3K4me1 as preferred substrate. Expression of Y4884C leads to aberrant H3K4me3 formation in cells. Our data show that different somatic cancer mutations of MLL3 affect the enzyme activity in distinct and opposing manner highlighting the importance of experimentally studying the effects of somatic cancer mutations in key regulatory
Kras: | |GTPase KRas| also known as |V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog| a... World Heritage Encyclopedia, the aggregation of the largest online encyclopedias available, and the most definitive collection ever assembled.
Mutation and recombination are central processes driving microbial evolution. A high mutation rate fuels adaptation but also generates deleterious mutations. Recombination between two different genomes may resolve this paradox, alleviating effects of clonal interference and purging deleterious mutations. Here we demonstrate that recombination significantly accelerates adaptation and evolution during acute virus infection. We identified a poliovirus recombination determinant within the virus polymerase, mutation of which reduces recombination rates without altering replication fidelity. By generating a panel of variants with distinct mutation rates and recombination ability, we demonstrate that recombination is essential to enrich the population in beneficial mutations and purge it from deleterious mutations. The concerted activities of mutation and recombination are key to virus spread and virulence in infected animals. These findings inform a mathematical model to demonstrate that poliovirus ...
The fluoroquinolones (FQs) are synthetic antibiotics effectively used for curing patients with multidrug-resistant tuberculosis (TB). When a multidrug-resistant strain develops resistance to the FQs, as in extensively drug-resistant strains, obtaining a cure is much more difficult, and molecular methods can help by rapidly identifying resistance-causing mutations. The only mutations proven to confer FQ resistance in M. tuberculosis occur in the FQ target, the DNA gyrase, at critical amino acids from both the gyrase A and B subunits that form the FQ binding pocket. GyrA substitutions are much more common and generally confer higher levels of resistance than those in GyrB. Molecular techniques to detect resistance mutations have suboptimal sensitivity because gyrase mutations are not detected in a variable percentage of phenotypically resistant strains. The inability to find gyrase mutations may be explained by heteroresistance: bacilli with a resistance-conferring mutation are present only in a ...
The emergence of drug resistance remains a major problem for the treatment of HIV-infected patients. However, the variety of mutational patterns that evolve in clinical practice have made the application of resistance data to clinical decision-making challenging. Despite (or because of) an abundance of drug-resistance data from disparate sources, there is only limited information available describing the patterns of drug resistance which usually appear in the clinic.
Interpreting cancer mutations is a complex task as only few mutations are cancer drivers while most are functionally inactive passengers (6). We can improve driver discovery by focusing on mutations in small sites involved in interactions of networks, as these mutations are more likely important in cancer. We used this idea to build the mutation enrichment model ActiveDriver (7) that analyses mutations in protein sites of post-translational modifications (PTMs). PTMs such as phosphorylation are involved in cellular signalling and cancer pathways. We applied ActiveDriver in the TCGA pan-cancer project to characterise the mutational landscape of signalling networks and to detect known and candidate cancer driver genes (8,9). In another study, we analysed population-wide genome variation and found that PTM sites are strongly conserved among humans and enriched in germline disease variants, emphasizing their importance in physiology and predisposition to disease (10). We recently developed the ...
Interpreting cancer mutations is a complex task as only few mutations are cancer drivers while most are functionally inactive passengers (6). We can improve driver discovery by focusing on mutations in small sites involved in interactions of networks, as these mutations are more likely important in cancer. We used this idea to build the mutation enrichment model ActiveDriver (7) that analyses mutations in protein sites of post-translational modifications (PTMs). PTMs such as phosphorylation are involved in cellular signalling and cancer pathways. We applied ActiveDriver in the TCGA pan-cancer project to characterise the mutational landscape of signalling networks and to detect known and candidate cancer driver genes (8,9). In another study, we analysed population-wide genome variation and found that PTM sites are strongly conserved among humans and enriched in germline disease variants, emphasizing their importance in physiology and predisposition to disease (10). We recently developed the ...
What are some restrictive conditions of the respiratory system? Visit HowStuffWorks to learn more about the respiratory system and some restrictive conditions of the respiratory system.
TY - JOUR. T1 - CAPN5 mutation in hereditary uveitis. T2 - The R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model. AU - Wert, Katherine J.. AU - Bassuk, Alexander G.. AU - Wu, Wen Hsuan. AU - Gakhar, Lokesh. AU - Coglan, Diana. AU - Mahajan, Mary Ann. AU - Wu, Shu. AU - Yang, Jing. AU - Lin, Chyuan Sheng. AU - Tsang, Stephen H.. AU - Mahajan, Vinit B.. PY - 2015/4/28. Y1 - 2015/4/28. N2 - A single amino acid mutation near the active site of the CAPN5 protease was linked to the inherited blinding disorder, autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM #193235). In homology modeling with other calpains, this R243L CAPN5 mutation was situated in a mobile loop that gates substrate access to the calcium-regulated active site. In in vitro activity assays, the mutation increased calpain protease activity and made it far more active at low concentrations of calcium. To test whether the disease allele could yield an ...
Loss of sex and recombination is generally assumed to impede the effectiveness of purifying selection and to result in the accumulation of slightly deleterious mutations. Empirical evidence for this has come from several studies investigating mutational load in a small number of individual genes. However, recent whole transcriptome based studies have yielded inconsistent results, hence questioning the validity of the assumption of mutational meltdown in asexual populations. Here, we study the effectiveness of purifying selection in eight asexual hexapod lineages and their sexual relatives, as present in the 1 K Insect Transcriptome Evolution (1KITE) project, covering eight hexapod groups. We analyse the accumulation of slightly deleterious nonsynonymous and synonymous point mutations in 99 single copy orthologue protein-coding loci shared among the investigated taxa. While accumulation rates of nonsynonymous mutations differed between genes and hexapod groups, we found no effect of reproductive mode on
References. Brosh, R., and Rotter, V. (2009). When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9, 701-713.. Dittmer, D., Pati, S., Zambetti, G., Chu, S., Teresky, A. K., Moore, M., Finlay, C., and Levine, A. J. (1993). Gain of function mutations in p53. Nat Genet 4, 42-46.. Gualberto, A., Aldape, K., Kozakiewicz, K., and Tlsty, T. D. (1998). An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci U S A 95, 5166-5171.. Lang, G. A., Iwakuma, T., Suh, Y. A., Liu, G., Rao, V. A., Parant, J. M., Valentin-Vega, Y. A., Terzian, T., Caldwell, L. C., Strong, L. C., El-Naggar, A. K., and Lozano, G. (2004). Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119, 861-872.. Olive, K. P., Tuveson, D. A., Ruhe, Z. C., Yin, B., Willis, N. A., Bronson, R. T., Crowley, D., and Jacks, T. (2004). Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell ...
Suggest two methods to isolate a collection of cold-sensitive mutants in Salmonella typhimurium -- that is, mutants that grow at 42 C but do not grow at 30 C.. ANSWER: Although conditional mutations may not grow at the nonpermissive temperature, they often survive short exposure to the nonpermissive temperature. With this hint, consider the three basic approaches for isolating mutants: selections, screens, and enrichments. There is no obvious way of selecting for the desired mutants because the desired mutation is unable to grow under the nonpermissive conditions. It would be straightforward to screen for the desired mutants -- for example, (i) you could plate colonies at 30 C, replica plate the colonies to 30 C and 42 C, then look for colonies that grow at 42 C but not at 30 C, or (ii) you could plate the cells at the nonpermissive temperature for a short time then shift the plates to the permissive temperature -- the mutants usually form smaller colonies due to the effect of the temporary ...
A high mutational load and the presence of a T-cell-inflamed environment may independently predict for treatment response to pembrolizumab (Keytruda) and progression-free survival, according to a study presented by Tanguy Seiwert, MD, of the University of Chicago, at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium.1. Nonsynonymous mutational load and neoantigen load as well as an 18-gene immune-related gene-expression profiling were significantly associated with overall response and progression-free survival to pembrolizumab across multiple indications, Dr. Seiwert revealed. This suggests that tumor antigenicity and T-cell infiltration may provide complementary information for expected pembrolizumab activity and may be useful in characterizing responses to immunotherapies, he said.. Tumor mutational load has been shown to correlate with benefit from drugs blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) in multiple tumor types. ...
Three temperature-sensitive S. cerevisiae RFA1 alleles were found to cause elevated mutation rates. These mutator phenotypes resulted from the accumulation of base substitutions, frameshifts, gross deletions (8 bp-18 kb), and nonreciprocal translocations. A representative rfa1 mutation exhibited a g …
With direct sanger sequencing, FemtoPath PTEN Mutation Screen Kit is able to detect somatic mutation from DNA derived from formalin-fixed paraffin-embedded (FFPET), fine needle biopsy or pleural effusion specimens.. The feature of FemtoPath mutation screen kit ...