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Internal Medicine (Tokyo, Japan) Nov 2023Objective Testing for the Janus activating kinase 2 (JAK2) V617F mutation is important for diagnosing and treating myeloproliferative neoplasms (MPNs). Recently, urine...
Objective Testing for the Janus activating kinase 2 (JAK2) V617F mutation is important for diagnosing and treating myeloproliferative neoplasms (MPNs). Recently, urine cell-free DNA (ucfDNA) was reported to be useful for detecting tumor-specific gene mutations in several solid tumors. However, its utility in detecting such mutations in hematological malignancies has not yet been assessed. In this study, we assessed whether or not the JAK2 V617F mutation could be detected in ucfDNA and whether or not its positivity rate in ucfDNA was associated with the JAK2 V617F allele ratio of peripheral blood cells in patients with MPN. Methods The JAK2 V617F allele ratio of genomic DNA from peripheral blood cells was determined using quantitative polymerase chain reaction (qPCR) or droplet digital PCR (ddPCR). ucfDNA was subjected to ddPCR. The correlation between the JAK2 V617F mutation positivity rates of blood-derived DNA and those of ucfDNA was assessed. Materials Twelve patients with polycythemia vera and 12 patients with essential thrombocythemia were enrolled. Ethylenediaminetetraacetic acid-treated peripheral blood (100 mL) and 15-30 mL of fresh urine were used. Results The JAK2 V617F mutation was detected in the ucfDNA from all 20 JAK2 V617F mutation-positive patients. In addition, the JAK2 V617F mutation positivity rate of ucfDNA was correlated with the JAK2 V617Fs allele ratio of blood-derived DNA, including in both estimated glomerular filtration rate (eGFR) groups (patients with an eGFR ≥50 or <50 mL/min/1.73 m). Conclusion Our results indicate that ucfDNA is a valuable tool for diagnosing and monitoring MPN. Given these findings, other disease-specific gene mutations in hematological malignancies may also be detectable in ucfDNA.
PubMed: 38008450
DOI: 10.2169/internalmedicine.2837-23 -
International Journal of Molecular... Sep 2023, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. alterations are found in 10% of gynecologic...
, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between mutation, increased tumor mutation burden (TMB), and immunotherapy response. This study evaluates the mutation frequency, association with TMB, and downstream effects of mutation in ovarian cancer. Genetic information, including whole-exome sequencing, RNA analysis, and somatic tumor testing, was obtained for consenting ovarian cancer patients at an academic medical center. Mutation frequencies were compared between the institutional cohort and The Cancer Genome Atlas (TCGA). Bioinformatics analyses were performed. In our cohort of 50 patients, 16 had a mutation, and 15 had recurrent disease. Median TMB for mutated patients was 25 compared to 7 for wild-type patients ( < 0.0001). Compared to the TCGA cohort, our cohort had higher mutation rates (32% vs. 6%, < 0.001). Gene expression related to immune cell trafficking, inflammatory response, and immune response (z > 2.0) was significantly increased in mutated patients. mutation is associated with increased TMB and immune cell infiltration in ovarian cancer and may serve as an additional biomarker for immunotherapy response.
Topics: Humans; Female; Ovarian Neoplasms; Mutation; Carcinoma, Ovarian Epithelial; Genital Neoplasms, Female; Mutation Rate; Cytoskeletal Proteins; Nerve Tissue Proteins
PubMed: 37762518
DOI: 10.3390/ijms241814212 -
PeerJ 2023is a species of Chinese medicinal plant, which has high medicinal and economic value and rich genetic diversity, but the study on its genetic diversity is far not... (Comparative Study)
Comparative Study
BACKGROUND
is a species of Chinese medicinal plant, which has high medicinal and economic value and rich genetic diversity, but the study on its genetic diversity is far not enough.
METHODS
In this study, one wild and one cultivated gardenia materials were resequenced using HiSeq sequencing platform and the data were evaluated to understand the genomic characteristics of s.
RESULTS
After data analysis, the results showed that clean data of 11.77G, Q30 reached 90.96%. The average comparison rate between the sample and reference genome was 96.08%, the average coverage depth was 15X, and the genome coverage was 85.93%. The SNPs of FD and YP1 were identified, and 3,087,176 and 3,241,416 SNPs were developed, respectively. In addition, SNP non-synonymous mutation, InDel mutation, SV mutation and CNV mutation were also detected between the sample and the reference genome, and KEGG, GO and COG database annotations were made for genes with DNA level variation. The structural gene variation in the biosynthetic pathway of crocin and gardenia, the main medicinal substance of was further explored, which provided basic data for molecular breeding and genetic diversity of s in the future.
Topics: Gardenia; Genomics; Plants, Medicinal; Sequence Analysis, DNA; China; Carotenoids; Genetic Variation
PubMed: 37744244
DOI: 10.7717/peerj.16056 -
PLoS Computational Biology Sep 2023Evolutionary dynamics in spatially structured populations has been studied for a long time. More recently, the focus has been to construct structures that amplify...
Evolutionary dynamics in spatially structured populations has been studied for a long time. More recently, the focus has been to construct structures that amplify selection by fixing beneficial mutations with higher probability than the well-mixed population and lower probability of fixation for deleterious mutations. It has been shown that for a structure to substantially amplify selection, self-loops are necessary when mutants appear predominately in nodes that change often. As a result, for low mutation rates, self-looped amplifiers attain higher steady-state average fitness in the mutation-selection balance than well-mixed populations. But what happens when the mutation rate increases such that fixation probabilities alone no longer describe the dynamics? We show that self-loops effects are detrimental outside the low mutation rate regime. In the intermediate and high mutation rate regime, amplifiers of selection attain lower steady-state average fitness than the complete graph and suppressors of selection. We also provide an estimate of the mutation rate beyond which the mutation-selection dynamics on a graph deviates from the weak mutation rate approximation. It involves computing average fixation time scaling with respect to the population sizes for several graphs.
Topics: Humans; Mutation; Mutation Rate; Biological Evolution; Exercise; Histological Techniques
PubMed: 37656739
DOI: 10.1371/journal.pcbi.1011387 -
BioRxiv : the Preprint Server For... Nov 2023Disentangling the effects of demography and selection has remained a focal point of population genetic analysis. Knowledge about mutation and recombination is essential...
Disentangling the effects of demography and selection has remained a focal point of population genetic analysis. Knowledge about mutation and recombination is essential in this endeavour; however, despite clear evidence that both mutation and recombination rates vary across genomes, it is common practice to model both rates as fixed. In this study, we quantify how this unaccounted for rate heterogeneity may impact inference using common approaches for inferring selection (DFE-alpha, Grapes, and polyDFE) and/or demography (fastsimcoal2 and ). We demonstrate that, if not properly modelled, this heterogeneity can increase uncertainty in the estimation of demographic and selective parameters and in some scenarios may result in mis-leading inference. These results highlight the importance of quantifying the fundamental evolutionary parameters of mutation and recombination prior to utilizing population genomic data to quantify the effects of genetic drift (., as modulated by demographic history) and selection; or, at the least, that the effects of uncertainty in these parameters can and should be directly modelled in downstream inference.
PubMed: 38014252
DOI: 10.1101/2023.11.11.566703 -
MedComm Oct 2023Tissue-type plasminogen activator (tPA) encoded by is a major mediator that promotes fibrinolysis and prevents thrombosis. Pathogenetic mutations in associated with...
Tissue-type plasminogen activator (tPA) encoded by is a major mediator that promotes fibrinolysis and prevents thrombosis. Pathogenetic mutations in associated with venous thromboembolism have rarely been reported. Here, we report the first case of a homozygous point mutation c.1411T>C (p.Y471H) in leading to thromboembolic events and conduct related functional studies. The corresponding tPA mutant protein (tPA-Y471H) and wild-type tPA (tPA-WT) were synthesized in vitro, and mutant mice ( mice) were constructed. The molecular docking and surface plasmon resonance results indicated that the mutation impeded the hydrogen-bonding interactions between the protease domain of tPA and the kringle 4 domain of plasminogen, and the binding affinity of tPA and plasminogen was significantly reduced with a difference of one order of magnitude. mRNA half-life assay showed that the half-life of tPA-Y471H was shortened. The inferior vena cava thrombosis model showed that the rate of venous thrombosis in mice was 80% compared with 53% in wild-type mice. Our data suggested a novel role for the protease domain of tPA in efficient plasminogen activation, and demonstrated that this tPA mutation could reduce the fibrinolysis function of the body and lead to an increased propensity for thrombosis.
PubMed: 37808270
DOI: 10.1002/mco2.392 -
Cancer Cell International Nov 2023Gastric cancer (GC) has emerged as a significant issue in public health all worldwide as a result of its high mortality rate and dismal prognosis. AT-rich interactive... (Review)
Review
Gastric cancer (GC) has emerged as a significant issue in public health all worldwide as a result of its high mortality rate and dismal prognosis. AT-rich interactive domain 1 A (ARID1A) is a vital component of the switch/sucrose-non-fermentable (SWI/SNF) chromatin remodeling complex, and ARID1A mutations occur in various tumors, leading to protein loss and decreased expression; it then affects the tumor biological behavior or prognosis. More significantly, ARID1A mutations will likely be biological markers for immune checkpoint blockade (ICB) treatment and selective targeted therapy. To provide theoretical support for future research on the stratification of individuals with gastric cancer with ARID1A as a biomarker to achieve precision therapy, we have focused on the clinical significance, predictive value, underlying mechanisms, and possible treatment strategies for ARID1A mutations in gastric cancer in this review.
PubMed: 38008753
DOI: 10.1186/s12935-023-03154-8 -
PLoS Genetics Dec 2023Clonal genome evolution is a key feature of asexually reproducing species and human cancer development. While many studies have described the landscapes of clonal genome...
Clonal genome evolution is a key feature of asexually reproducing species and human cancer development. While many studies have described the landscapes of clonal genome evolution in cancer, few determine the underlying evolutionary parameters from molecular data, and even fewer integrate theory with data. We derived theoretical results linking mutation rate, time, expansion dynamics, and biological/clinical parameters. Subsequently, we inferred time-resolved estimates of evolutionary parameters from mutation accumulation, mutational signatures and selection. We then applied this framework to predict the time of speciation of the marbled crayfish, an enigmatic, globally invasive parthenogenetic freshwater crayfish. The results predict that speciation occurred between 1986 and 1990, which is consistent with biological records. We also used our framework to analyze whole-genome sequencing datasets from primary and relapsed glioblastoma, an aggressive brain tumor. The results identified evolutionary subgroups and showed that tumor cell survival could be inferred from genomic data that was generated during the resection of the primary tumor. In conclusion, our framework allowed a time-resolved, integrated analysis of key parameters in clonally evolving genomes, and provided novel insights into the evolutionary age of marbled crayfish and the progression of glioblastoma.
Topics: Animals; Humans; Glioblastoma; Genome; Astacoidea; Genomics; Biological Evolution; Mutation
PubMed: 38096267
DOI: 10.1371/journal.pgen.1011085 -
Genome Medicine Aug 2023Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and...
BACKGROUND
Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and functional region preferences. As a result, some sequence contexts mutate at much higher rates than others, with additional variation found between functional regions. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes.
METHODS
We count the 11-mer genomic sequences across the genome, and using the PCAWG set of 2583 pan-cancer whole genomes, we associate 11-mers with mutational signatures, hotspots of single nucleotide variants, and specific genomic regions. We evaluate the mutation rates of individual and combined sets of 11-mers and derive mutational sequence motifs.
RESULTS
We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE deficiency), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate and sequence preference increase further when focusing on certain genomic regions, such as signature 62 in transcribed regions, where the mutation rate is increased up to 9-folds over cancer type and mutational signature average.
CONCLUSIONS
We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.
Topics: Humans; Mutation Rate; Mutation; Neoplasms; DNA Damage; Genomics
PubMed: 37592287
DOI: 10.1186/s13073-023-01217-z -
Frontiers in Neurology 2023This study aimed to examine the clinical and gene-mutation characteristics of pediatric patients with sodium channel gene mutation-related childhood epilepsy and to...
OBJECTIVE
This study aimed to examine the clinical and gene-mutation characteristics of pediatric patients with sodium channel gene mutation-related childhood epilepsy and to provide a basis for precision treatment and genetic counseling.
METHODS
The clinical data from 94 patients with sodium channel gene mutation-related childhood epilepsy who were treated at Hunan Children's Hospital from August 2012 to December 2022 were retrospectively evaluated, and the clinical characteristics, gene variants, treatment, and follow-up status were analyzed and summarized.
RESULTS
Our 94 pediatric patients with sodium channel gene variant-related childhood epilepsy comprised 37 girls and 57 boys. The age of disease onset ranged from 1 day to 3 years. We observed seven different sodium channel gene variants, and 55, 14, 9, 6, 6, 2, and 2 patients had , and variants, respectively. We noted that 52 were reported variants and 42 were novel variants. Among all gene types, , and variants were associated with an earlier disease onset age. With the exception of the , the other six genes were associated with clustering seizures. Except for variants and , some patients with other variants had status epilepticus (SE). The main diagnosis of children with variants was Dravet syndrome (DS) (72.7%), whereas patients with and variants were mainly diagnosed with various types of epileptic encephalopathy, accounting for 85.7% (12 of 14) and 88.9% (8 of 9) respectively. A total of five cases of sudden unexpected death in epilepsy (SUDEP) occurred in patients with , and variants. The proportion of benign epilepsy in patients with , and variants was relatively high, and the epilepsy control rate was higher than the rate of other variant types.
CONCLUSION
Sodium channel gene variants involve different epileptic syndromes, and the treatment responses also vary. We herein reported 42 novel variants, and we are also the first ever to report two patients with variants, thereby increasing the gene spectrum and phenotypic profile of sodium channel dysfunction. We provide a basis for precision treatment and prognostic assessment.
PubMed: 38174099
DOI: 10.3389/fneur.2023.1310419