Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of ...limited access to tumor tissue.
We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.
We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.
The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.
Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We ...applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.
Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a ...framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored.
By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant (SSV) breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs. Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration.
Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.
A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohorts and cancer types, can provide insight into cancer-relevant alterations outside of exomes. By ...integrative analysis of whole-genome sequencing (predominantly low pass) and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression. While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes—including overexpressed cancer driver genes (e.g., TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (e.g., TP53, RB1, PTEN, STK11)—show SV-associated deregulation independent of CNA. SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene upregulation. For cancer-relevant pathways, SVs considerably expand our understanding of how genes are affected beyond point mutation or CNA.
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•Whole-genome analysis of >1,400 cancer cases by high- or low-pass sequencing•Hundreds of genes with overexpression associated with somatic structural variants•Structural variant breakpoints within specific tumor suppressors disrupt expression•No single mechanism involved with structural variant-mediated gene deregulation
Zhang et al. analyzed over 1,400 cancers by high- or low-pass whole-genome sequencing, focusing on patterns of structural variation. They saw a widespread impact of somatic structural variants on gene expression patterns, independent of copy-number alterations, involving key oncogenes and tumor suppressor genes.
Although the essential function of checkpoint kinase 1 (Chkl) in DNA damage response has been well established, the role of Chkl in normal cell cycle progression is unclear. By using RNAi to ...specifically deplete Chkl, we determined loss-of-function phenotypes in HeLa cells. A vector-based RNAi approach showed that Chkl is required for normal cell proliferation and survival, inasmuch as a dramatic cell-cycle arrest at G₂/M phase and massive apoptosis were observed in Chkl-deficient cells. Coupling of siRNA with cell synchronization further revealed that Chkl depletion leads to metaphase block, as indicated by various mitotic markers. Neither bipolar spindle formation nor centrosome functions were affected by Chkl depletion; however, the depleted cells exhibited chromosome misalignment during metaphase, chromosome lagging during anaphase, and kinetochore defects within the regions of misaligned/lagging chromosomes. Moreover, we showed that Chkl is a negative regulator of polo-like kinase 1 (Plkl), in either the absence or presence of DNA damage. Finally, Chkl depletion leads to the activation of the spindle checkpoint because codepletion of spindle checkpoint proteins rescues the Chkl depletioninduced mitotic arrest.
Platinum group compounds are currently the best performance hydrogen evolution catalysts, but their high price and low abundance limit their large-scale applications. Therefore, noble-metal-free ...catalysts have become a focus in the research of hydrogen evolution reactions (HER). In this work, we developed a noble-metal-free HER catalyst consisting of Co
3
O
4
supported on N-doped carbon nanotubes (Co
3
O
4
-NCTs). The Co
3
O
4
-NCT catalyst synthesized by stirring, heating, and high-temperature calcination was studied, showing a very low Tafel plot (32.3 mV dec
−1
) in an alkaline solution and good stability for hydrogen evolution reactions. In addition, the material synthesis method is simple, the experimental raw materials are cheap and easy to obtain, and it is expected to be suitable for large-scale industrial production.
Using high quality sequence reads extracted from our whole genome shotgun repository, we assembled two chloroplast genome sequences from two rice (Oryza sativa) varieties, one from 93-11 (a typical ...indica variety) and the other from PA64S (an indica-like variety with maternal origin of japonica), which are both parental varieties of the super-hybrid rice, LYP9. Based on the patterns of high sequence coverage, we partitioned chloroplast sequence variations into two classes, intravarietal and intersubspecific polymorphisms. Intravarietal polymorphisms refer to variations within 93-11 or PA64S. Intersubspecific polymorphisms were identified by comparing the major genotypes of the two subspecies represented by 93-11 and PA64S, respectively. Some of the minor genotypes occurring as intravarietal polymorphisms in one variety existed as major genotypes in the other subspecific variety, thus giving rise to intersubspecific polymorphisms. In our study, we found that the intersubspecific variations of 93-11 (indica) and PA64S (japonica) chloroplast genomes consisted of 72 single nucleotide polymorphisms and 27 insertions or deletions. The intersubspecific polymorphism rates between 93-11 and PA64S were 0.05% for single nucleotide polymorphisms and 0.02% for insertions or deletions, nearly 8 and 10 times lower than their respective nuclear genomes. Based on the total number of nucleotide substitutions between the two chloroplast genomes, we dated the divergence of indica and japonica chloroplast genomes as occurring approximately 86,000 to 200,000 years ago.
Exosomes are small vesicles (50–150 nm) of endocytic origin that are released by many different cell types. Exosomes in the tumor microenvironment may play a key role in facilitating cell-cell ...communication. Exosomes are reported to predominantly contain RNA and proteins. In this study, we investigated whether exosomes from pancreatic cancer cells and serum from patients with pancreatic ductal adenocarcinoma contain genomic DNA. Our results provide evidence that exosomes contain >10-kb fragments of double-stranded genomic DNA. Mutations in KRAS and p53 can be detected using genomic DNA from exosomes derived from pancreatic cancer cell lines and serum from patients with pancreatic cancer. In addition, using whole genome sequencing, we demonstrate that serum exosomes from patients with pancreatic cancer contain genomic DNA spanning all chromosomes. These results indicate that serum-derived exosomes can be used to determine genomic DNA mutations for cancer prediction, treatment, and therapy resistance.
Exosomes are small vesicles in the tumor microenvironment containing nucleic acids and proteins with the capacity to influence cell behavior.
Exosomes contain double-stranded genomic DNA.
Exosomes have the capacity to carry and transport genomic DNA spanning all chromosomes with KRAS and p53 mutations.
Exosomes can aid in identifying genomic mutations in patients with pancreatic cancer.
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•A simple and effective synthesis route for quantum dots is proposed.•The combination of 0 D and 3 D materials improves electrocatalytic activity.•The catalyst shows excellent ...electrocatalytic hydrogen evolution performance.•The ΔGH* of electrocatalyst is calculated by density functional theory (DFT).
Hydrogen energy has become one of the most potential sources for replacing fossil fuels due to its environmental friendliness and high energy conversion rate. Electrolyzed water is a hydrogen evolution process with high efficiency, no by-products, and high hydrogen purity. Here, we propose to use ZIF-67 as the precursor to prepare three-dimensional multilayer rGO supported CoS2 quantum dots (CoS2QDs@rGO) through a two-step hydrothermal method and one-step calcinations method. The as-prepared electrocatalyst with maximum exposure of edge active sites is highly efficient for hydrogen evolution reaction (HER), delivering an extremely small Tafel slope of 78 mV dec-1, and prominent durability. Density functional theory (DFT) calculations reveal that decoration of CoS2QDs not only obviously changes Gibbs free energy of hydrogen adsorption (ΔGH*), but also offers more active sites for HER, conspicuous promoting the catalytic activity of as-obtained electrode materials. It can be expected that our CoS2 quantum dots mounted on three-dimensional multilayer rGO with ZIF-67 as the precursor, will provide a novel, high-yield and effective catalytic material for energy conversion applications.
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