Publications by authors named "Ivan Smirnov"

93 Publications

Drift of the Subgingival Periodontal Microbiome during Chronic Periodontitis in Type 2 Diabetes Mellitus Patients.

Pathogens 2021 Apr 22;10(5). Epub 2021 Apr 22.

Ministry of Healthcare of the Russian Federation, A.I. Evdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia.

Since periodontitis and type 2 diabetes mellitus are complex diseases, a thorough understanding of their pathogenesis requires knowing the relationship of these pathologies with other disorders and environmental factors. In this study, the representability of the subgingival periodontal microbiome of 46 subjects was studied by 16S rRNA gene sequencing and shotgun sequencing of pooled samples. We examined 15 patients with chronic periodontitis (CP), 15 patients with chronic periodontitis associated with type 2 diabetes mellitus (CPT2DM), and 16 healthy subjects (Control). The severity of generalized chronic periodontitis in both periodontitis groups of patients (CP and CPT2DM) was moderate (stage II). The male to female ratios were approximately equal in each group (22 males and 24 females); the average age of the subjects was 53.9 ± 7.3 and 54.3 ± 7.2 years, respectively. The presence of overweight patients (Body Mass Index (BMI) 30-34.9 kg/m) and patients with class 1-2 obesity (BMI 35-45.9 kg/m) was significantly higher in the CPT2DM group than in patients having only chronic periodontitis or in the Control group. However, there was no statistically significant difference in all clinical indices between the CP and CPT2DM groups. An analysis of the metagenomic data revealed that the alpha diversity in the CPT2DM group was increased compared to that in the CP and Control groups. The microbiome biomarkers associated with experimental groups were evaluated. In both groups of patients with periodontitis, the relative abundance of was increased compared to that in the Control group. The CPT2DM group was characterized by a lower relative abundance of / and a higher abundance of compared to those in the CP and Control groups. Furthermore, the CP and CPT2DM groups differed in terms of the relative abundance of (which was decreased in the CPT2DM group compared to CP) and (which was increased in the CPT2DM group compared to CP). In addition, differences in bacterial content were identified by a combination of shotgun sequencing of pooled samples and genome-resolved metagenomics. The results indicate that there are subgingival microbiome-specific features in patients with chronic periodontitis associated with type 2 diabetes mellitus.
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http://dx.doi.org/10.3390/pathogens10050504DOI Listing
April 2021

Structure and Phase Composition of a W-Ta-Mo-Nb-V-Cr-Zr-Ti Alloy Obtained by Ball Milling and Spark Plasma Sintering.

Entropy (Basel) 2020 Jan 24;22(2). Epub 2020 Jan 24.

Lavrentyev Institute of Hydrodynamics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.

In this paper, the structural characteristics of a W-Ta-Mo-Nb-V-Cr-Zr-Ti non-equiatomic refractory metal alloy obtained by spark plasma sintering (SPS) of a high-energy ball-milled powder mixture are reported. High-energy ball milling resulted in the formation of particle agglomerates ranging from several tens to several hundreds of micrometers. These agglomerates were composed of micrometer and submicrometer particles. It was found that, during ball milling, a solid solution of A2 structure formed. The grains of the sintered material ranged from fractions of a micrometer to several micrometers. During SPS, the phase transformations in the alloy led to the formation of a Laves phase of C15 structure and ZrO and ZrO nanoparticles. The microhardness of the ball-milled alloy and sintered material was found to be 9.28 GPa ± 1.31 GPa and 8.95 GPa ± 0.42 GPa, respectively. The influence of the processing conditions on the structure, phase composition, and microhardness of the alloy is discussed.
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http://dx.doi.org/10.3390/e22020143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516556PMC
January 2020

Liquid drop of DNA libraries reveals total genome information.

Proc Natl Acad Sci U S A 2020 11 21;117(44):27300-27306. Epub 2020 Oct 21.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia;

Conventional "bulk" PCR often yields inefficient and nonuniform amplification of complex templates in DNA libraries, introducing unwanted biases. Amplification of single DNA molecules encapsulated in a myriad of emulsion droplets (emulsion PCR, ePCR) allows the mitigation of this problem. Different ePCR regimes were experimentally analyzed to identify the most robust techniques for enhanced amplification of DNA libraries. A phenomenological mathematical model that forms an essential basis for optimal use of ePCR for library amplification was developed. A detailed description by high-throughput sequencing of amplified DNA-encoded libraries highlights the principal advantages of ePCR over bulk PCR. ePCR outperforms PCR, reduces gross DNA errors, and provides a more uniform distribution of the amplified sequences. The quasi single-molecule amplification achieved via ePCR represents the fundamental requirement in case of complex DNA templates being prone to diversity degeneration and provides a way to preserve the quality of DNA libraries.
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http://dx.doi.org/10.1073/pnas.2017138117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959537PMC
November 2020

A Strategy for Tumor Targeting by Higher-Order Glycan Pattern Recognition: Synthesis and In Vitro and In Vivo Properties of Glycoalbumins Conjugated with Four Different N-Glycan Molecules.

Small 2020 11 20;16(46):e2004831. Epub 2020 Oct 20.

Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.

Natural glycoconjugates that form glycocalyx play important roles in various biological processes based on cell surface recognition through pattern recognition mechanisms. This work represents a new synthesis-based screening strategy to efficiently target the cancer cells by higher-order glycan pattern recognition in both cells and intact animals (mice). The use of the very fast, selective, and effective RIKEN click reaction (6π-azaelectrocyclization of unsaturated imines) allows to synthesize and screen various structurally well-defined glycoalbumins containing two and eventually four different N-glycan structures in a very short time. The importance of glycan pattern recognition is exemplified in both cell- and mouse-based experiments. The use of pattern recognition mechanisms for cell targeting represents a novel and promising strategy for the development of diagnostic, prophylactic, and therapeutic agents for various diseases including cancers.
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http://dx.doi.org/10.1002/smll.202004831DOI Listing
November 2020

Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers.

Proc Natl Acad Sci U S A 2020 09 28;117(37):22841-22848. Epub 2020 Aug 28.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

Quantum mechanics/molecular mechanics (QM/MM) maturation of an immunoglobulin (Ig) powered by supercomputation delivers novel functionality to this catalytic template and facilitates artificial evolution of biocatalysts. We here employ density functional theory-based (DFT-b) tight binding and funnel metadynamics to advance our earlier QM/MM maturation of A17 Ig-paraoxonase (WTIgP) as a reactibody for organophosphorus toxins. It enables regulation of biocatalytic activity for tyrosine nucleophilic attack on phosphorus. The single amino acid substitution l-Leu47Lys results in 340-fold enhanced reactivity for paraoxon. The computed ground-state complex shows substrate-induced ionization of the nucleophilic l-Tyr37, now H-bonded to l-Lys47, resulting from repositioning of l-Lys47. Multiple antibody structural homologs, selected by phenylphosphonate covalent capture, show contrasting enantioselectivities for a P-chiral phenylphosphonate toxin. That is defined by crystallographic analysis of phenylphosphonylated reaction products for antibodies A5 and WTIgP. DFT-b analysis using QM regions based on these structures identifies transition states for the favored and disfavored reactions with surprising results. This stereoselection analysis is extended by funnel metadynamics to a range of WTIgP variants whose predicted stereoselectivity is endorsed by experimental analysis. The algorithms used here offer prospects for tailored design of highly evolved, genetically encoded organophosphorus scavengers and for broader functionalities of members of the Ig superfamily, including cell surface-exposed receptors.
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http://dx.doi.org/10.1073/pnas.2010317117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502716PMC
September 2020

Sodium action potentials in placozoa: Insights into behavioral integration and evolution of nerveless animals.

Biochem Biophys Res Commun 2020 10 20;532(1):120-126. Epub 2020 Aug 20.

Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL, 32080, USA; Department of Neuroscience and McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA. Electronic address:

Placozoa are small disc-shaped animals, representing the simplest known, possibly ancestral, organization of free-living animals. With only six morphological distinct cell types, without any recognized neurons or muscle, placozoans exhibit fast effector reactions and complex behaviors. However, little is known about electrogenic mechanisms in these animals. Here, we showed the presence of rapid action potentials in four species of placozoans (Trichoplax adhaerens [H1 haplotype], Trichoplax sp.[H2], Hoilungia hongkongensis [H13], and Hoilungia sp. [H4]). These action potentials are sodium-dependent and can be inducible. The molecular analysis suggests the presence of 5-7 different types of voltage-gated sodium channels, which showed substantial evolutionary radiation compared to many other metazoans. Such unexpected diversity of sodium channels in early-branched metazoan lineages reflect both duplication events and parallel evolution of unique behavioral integration in these nerveless animals.
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http://dx.doi.org/10.1016/j.bbrc.2020.08.020DOI Listing
October 2020

Selective Eradication of by the Designer Genetically Programmed Yeast Biocontrol Agent.

Antibiotics (Basel) 2020 Aug 19;9(9). Epub 2020 Aug 19.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia.

is a common human pathogen that is particularly often associated with antibiotic resistance. The eradication of this ubiquitous infectious agent from its ecological niches and contaminated surfaces is especially complicated by excessive biofilm formation and persisting cells, which evade the antibacterial activity of conventional antibiotics. Here, we present an alternative view of the problem of specific eradication. The constitutive heterologous production of highly specific bacteriolytic protease lysostaphin in yeast provides an efficient biocontrol agent, specifically killing in coculture. A yeast-based anti- probiotic was efficient in a high range of temperatures and target-to-effector ratios, indicating its robustness and versatility in eliminating cells. The efficient eradication of by live lysostaphin-producing was achieved at high scales, providing a simple, biocompatible and cost-effective strategy for lysis in bioproduction and surface decontamination. Future biomedical applications based on designer yeast biocontrol agents require evaluation in in vivo models. However, we believe that this strategy is very promising since it provides highly safe, efficient and selective genetically programmed probiotics and targeted biocontrol agents.
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http://dx.doi.org/10.3390/antibiotics9090527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559405PMC
August 2020

A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding.

Sci Adv 2020 Jun 24;6(26):eaaz9861. Epub 2020 Jun 24.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia.

Microbial communities are self-controlled by repertoires of lethal agents, the antibiotics. In their turn, these antibiotics are regulated by bioscavengers that are selected in the course of evolution. Kinase-mediated phosphorylation represents one of the general strategies for the emergence of antibiotic resistance. A new subfamily of AmiN-like kinases, isolated from the Siberian bear microbiome, inactivates antibiotic amicoumacin by phosphorylation. The nanomolar substrate affinity defines AmiN as a phosphotransferase with a unique catalytic efficiency proximal to the diffusion limit. Crystallographic analysis and multiscale simulations revealed a catalytically perfect mechanism providing phosphorylation exclusively in the case of a closed active site that counteracts substrate promiscuity. AmiN kinase is a member of the previously unknown subfamily representing the first evidence of a specialized phosphotransferase bioscavenger.
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http://dx.doi.org/10.1126/sciadv.aaz9861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314540PMC
June 2020

Deep Functional Profiling Facilitates the Evaluation of the Antibacterial Potential of the Antibiotic Amicoumacin.

Antibiotics (Basel) 2020 Apr 2;9(4). Epub 2020 Apr 2.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia.

The global spread of antibiotic resistance is forcing the scientific community to find new molecular strategies to counteract it. Deep functional profiling of microbiomes provides an alternative source for the discovery of novel antibiotic producers and probiotics. Recently, we implemented this ultrahigh-throughput screening approach for the isolation of strains efficiently producing the ribosome-targeting antibiotic amicoumacin A (Ami). Proteomics and metabolomics revealed essential insight into the activation of Ami biosynthesis. Here, we applied omics to boost Ami biosynthesis, providing the optimized cultivation conditions for high-scale production of Ami. Ami displayed a pronounced activity against and , including methicillin-resistant (MRSA) strains, which was determined using both classical and massive single-cell microfluidic assays. However, the practical application of Ami is limited by its high cytotoxicity and particularly low stability. The former is associated with its self-lactonization, serving as an improvised intermediate state of Ami hydrolysis. This intramolecular reaction decreases Ami half-life at physiological conditions to less than 2 h, which is unprecedented for a terminal amide. While we speculate that the instability of Ami is essential for ecology, we believe that its stable analogs represent attractive lead compounds both for antibiotic discovery and for anticancer drug development.
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http://dx.doi.org/10.3390/antibiotics9040157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235827PMC
April 2020

Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides.

Front Immunol 2019 17;10:3088. Epub 2020 Jan 17.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.

Risk of the development of multiple sclerosis (MS) is known to be increased in individuals bearing distinct class II human leukocyte antigen (HLA) variants, whereas some of them may have a protective effect. Here we analyzed distribution of a highly polymorphous HLA- locus in more than one thousand relapsing-remitting MS patients and healthy individuals of Russian ethnicity. Carriage of HLA*15 and HLA*03 alleles was associated with MS risk, whereas carriage of HLA*01 and HLA*11 was found to be protective. Analysis of genotypes revealed the compensatory effect of risk and resistance alleles . We have identified previously unknown MBP peptide located at the C-terminus of MBP protein and MBP peptide that bound to recombinant HLA-DRB1*01:01 protein with affinity comparable to that of classical antigenic peptide 306-318 from the hemagglutinin (HA) of the influenza virus demonstrating the ability of HLA-DRB1*01:01 to present newly identified MBP and MBP peptides. Measurements of kinetic parameters of MBP and HA peptides binding to HLA-DRB1*01:01 catalyzed by HLA-DM revealed a significantly lower rate of CLIP exchange for MBP and MBP peptides as opposed to HA peptide. Analysis of the binding of chimeric MBP-HA peptides demonstrated that the observed difference between MBP, MBP, and HA peptide epitopes is caused by the lack of anchor residues in the C-terminal part of the MBP peptides resulting in a moderate occupation of P6/7 and P9 pockets of HLA-DRB1*01:01 by MBP and MBP peptides in contrast to HA peptide. This leads to the P1 and P4 docking failure and rapid peptide dissociation and release of empty HLA-DM-HLA-DR complex. We would like to propose that protective properties of the HLA*01 allele could be directly linked to the ability of HLA-DRB1*01:01 to kinetically discriminate between antigenic exogenous peptides and endogenous MBP derived peptides.
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http://dx.doi.org/10.3389/fimmu.2019.03088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978714PMC
November 2020

Facile Access to Optically Active 2,6-Dialkyl-1,5-Diazacyclooctanes.

Chem Asian J 2019 Nov 13;14(22):4048-4054. Epub 2019 Aug 13.

Biofunctional Chemistry Laboratory, Alexander Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya Street, Kazan, 420008, Russia.

The chiral substituted 1,5-diazacyclooctane (1,5-DACO) is of considerable importance and has attracted attention from a wide range of fields due to their unique chemical and biological properties. Despite the application potential, further study has not been optimized due to difficulties in their synthetic accessibility. Here, we report that the 1,5-DACO bearing a chiral auxiliary obtained from the formal [4+4] cycloaddition of N-alkyl-α,β-unsaturated imines can be further derivatized by nucleophilic alkylation to give various chiral substituted 1,5-DACO derivatives. The removal of the chiral auxiliary was effectively carried out using hydrogenation over Pearlman's catalyst. This methodology allows the production of a broad range of unprecedented optically active 2,6-dialkyl-1,5-DACO, which could not be accessed by other methods.
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http://dx.doi.org/10.1002/asia.201900938DOI Listing
November 2019

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Blood 2019 10;134(15):1227-1237

Department of Paediatric and Adolescent Oncology, University of Manchester, Manchester, United Kingdom.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.
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http://dx.doi.org/10.1182/blood.2018890764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788009PMC
October 2019

Schools are segregated by educational outcomes in the digital space.

Authors:
Ivan Smirnov

PLoS One 2019 28;14(5):e0217142. Epub 2019 May 28.

Institute of Education, National Research University Higher School of Economics, Moscow, Russia.

The Internet provides students with a unique opportunity to connect and maintain social ties with peers from other schools, irrespective of how far they are from each other. However, little is known about the real structure of such online relationships. In this paper, we investigate the structure of interschool friendship on a popular social networking site. We use data from 36, 951 students from 590 schools of a large European city. We find that the probability of a friendship tie between students from neighboring schools is high and that it decreases with the distance between schools following the power law. We also find that students are more likely to be connected if the educational outcomes of their schools are similar. We show that this fact is not a consequence of residential segregation. While high- and low-performing schools are evenly distributed across the city, this is not the case for the digital space, where schools turn out to be segregated by educational outcomes. There is no significant correlation between the educational outcomes of a school and its geographical neighbors; however, there is a strong correlation between the educational outcomes of a school and its digital neighbors. These results challenge the common assumption that the Internet is a borderless space, and may have important implications for the understanding of educational inequality in the digital age.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217142PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538368PMC
January 2020

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.

Genes Chromosomes Cancer 2019 10 27;58(10):723-730. Epub 2019 May 27.

Center for Genetic Epidemiology, Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California.

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10 ), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.
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http://dx.doi.org/10.1002/gcc.22765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684857PMC
October 2019

Charge-mediated proteasome targeting.

FASEB J 2019 06 27;33(6):6852-6866. Epub 2019 Feb 27.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.

A majority of thousands of intracellular mammalian proteins are recognized by proteasome only being conjugated with ubiquitin (Ub), representing a universal degradation signal operated by the ubiquitination system. Ub-independent proteasome targeting is rationalized by the existence of 2 types of direct proteasome signals (DPSs), specific amino acid sequences or post-translational modifications, which are recognized by proteasome regulatory subunits. Historically, the first type was shown to exist in ornithine decarboxylase, whereas acetylation of core histones recently was reported as a second type of DPS. Here we declare a third type, representing charge-mediated DPS. This discovered DPS may be classified as a monopartite composition- but not sequence-dependent element of ∼70 Å in length enriched in basic and flexible amino acids. This type of degradation signal, which may be provided by cationic chemicals, is most efficiently engaged by proteasomes capped with regulator (REG)α or REGγ in an ATP-independent manner. Taken together, our findings suggest a novel modality of proteasome-substrate interrelation bypassing ubiquitination.-Kudriaeva, A., Kuzina, E. S., Zubenko, O., Smirnov, I. V., Belogurov, A. Charge-mediated proteasome targeting.
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http://dx.doi.org/10.1096/fj.201802237RDOI Listing
June 2019

Longer genotypically-estimated leukocyte telomere length is associated with increased meningioma risk.

J Neurooncol 2019 May 22;142(3):479-487. Epub 2019 Feb 22.

Department of Neurosurgery, Brigham and Woman's Hospital, Boston, MA, USA.

Purpose: Telomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls.

Methods/patients: One thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP's genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates.

Results: Three out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR 1.14, 95% CI 1.01-1.28, rs2736100: OR 1.13, 95% CI 1.03-1.25, rs9420907: OR 1.22, 95% CI 1.07-1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2 bp (standard error (SE): 4.05 bp), mean controls: 541.5 bp (SE: 2.02 bp), logistic regression p value = 2.13 × 10].

Conclusion: Increased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.
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http://dx.doi.org/10.1007/s11060-019-03119-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482066PMC
May 2019

Mendelian randomization provides support for obesity as a risk factor for meningioma.

Sci Rep 2019 01 22;9(1):309. Epub 2019 Jan 22.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

Little is known about the causes of meningioma. Obesity and obesity-related traits have been reported in several epidemiological observational studies to be risk factors for meningioma. We performed an analysis of genetic variants associated with obesity-related traits to assess the relationship with meningioma risk using Mendelian randomization (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. We considered 11 obesity-related traits, identified genetic instruments for these factors, and assessed their association with meningioma risk using data from a genome-wide association study comprising 1,606 meningioma patients and 9,823 controls. To evaluate the causal relationship between the obesity-related traits and meningioma risk, we consider the estimated odds ratio (OR) of meningioma for each genetic instrument. We identified positive associations between body mass index (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (OR = 1.28, 95% CI = 1.01-1.63, P = 0.042) with meningioma risk, albeit non-significant after correction for multiple testing. Associations for basal metabolic rate, diastolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, total cholesterol, triglycerides and waist circumference with risk of meningioma were non-significant. Our analysis provides additional support for obesity being associated with an increased risk of meningioma.
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http://dx.doi.org/10.1038/s41598-018-36186-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343031PMC
January 2019

Parents mention sons more often than daughters on social media.

Proc Natl Acad Sci U S A 2019 02 22;116(6):2039-2041. Epub 2019 Jan 22.

Institute of Education, National Research University Higher School of Economics, Moscow 101000, Russia

Gender inequality starts early in life. Parents tend to prefer boys over girls, which is manifested in reproductive behavior, marital life, and parents' pastimes and investments in their children. While social media and sharing information about children (so-called "sharenting") have become an integral part of parenthood, whether and how gender preference shapes the online behavior of users are not well known. In this paper we use public posts made by 635,665 users from Saint Petersburg on a popular Russian social networking site, to investigate public mentions of daughters and sons on social media. We find that both men and women mention sons more often than daughters in their posts. We also find that posts featuring sons receive more "likes" on average. Our results indicate that girls are underrepresented in parents' digital narratives about their children, in a country with an above-average ranking on gender parity. This gender imbalance may send a message that girls are less important than boys or that they deserve less attention, thus reinforcing gender inequality from an early age.
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http://dx.doi.org/10.1073/pnas.1804996116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369760PMC
February 2019

Genetically encodable bioluminescent system from fungi.

Proc Natl Acad Sci U S A 2018 12 26;115(50):12728-12732. Epub 2018 Nov 26.

Departamento de Oceanografia Física, Química e Geológica, Instituto Oceanográfico, Universidade de São Paulo, 05508-120 São Paulo, Brazil.

Bioluminescence is found across the entire tree of life, conferring a spectacular set of visually oriented functions from attracting mates to scaring off predators. Half a dozen different luciferins, molecules that emit light when enzymatically oxidized, are known. However, just one biochemical pathway for luciferin biosynthesis has been described in full, which is found only in bacteria. Here, we report identification of the fungal luciferase and three other key enzymes that together form the biosynthetic cycle of the fungal luciferin from caffeic acid, a simple and widespread metabolite. Introduction of the identified genes into the genome of the yeast along with caffeic acid biosynthesis genes resulted in a strain that is autoluminescent in standard media. We analyzed evolution of the enzymes of the luciferin biosynthesis cycle and found that fungal bioluminescence emerged through a series of events that included two independent gene duplications. The retention of the duplicated enzymes of the luciferin pathway in nonluminescent fungi shows that the gene duplication was followed by functional sequence divergence of enzymes of at least one gene in the biosynthetic pathway and suggests that the evolution of fungal bioluminescence proceeded through several closely related stepping stone nonluminescent biochemical reactions with adaptive roles. The availability of a complete eukaryotic luciferin biosynthesis pathway provides several applications in biomedicine and bioengineering.
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http://dx.doi.org/10.1073/pnas.1803615115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294908PMC
December 2018

NTnC-like genetically encoded calcium indicator with a positive and enhanced response and fast kinetics.

Sci Rep 2018 10 15;8(1):15233. Epub 2018 Oct 15.

Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia.

The NTnC genetically encoded calcium indicator has an advantageous design because of its smaller size, GFP-like N- and C-terminal ends and two-fold reduced number of calcium binding sites compared with widely used indicators from the GCaMP family. However, NTnC has an inverted and modest calcium response and a low temporal resolution. By replacing the mNeonGreen fluorescent part in NTnC with EYFP, we engineered an NTnC-like indicator, referred to as YTnC, that had a positive and substantially improved calcium response and faster kinetics. YTnC had a 3-fold higher calcium response and 13.6-fold lower brightness than NTnC in vitro. According to stopped-flow experiments performed in vitro, YTnC had 4-fold faster calcium-dissociation kinetics than NTnC. In HeLa cells, YTnC exhibited a 3.3-fold lower brightness and 4.9-fold increased response to calcium transients than NTnC. The spontaneous activity of neuronal cultures induced a 3.6-fold larger ΔF/F response of YTnC than previously shown for NTnC. On patched neurons, YTnC had a 2.6-fold lower ΔF/F than GCaMP6s. YTnC successfully visualized calcium transients in neurons in the cortex of anesthetized mice and the hippocampus of awake mice using single- and two-photon microscopy. Moreover, YTnC outperformed GCaMP6s in the mitochondria and endoplasmic reticulum of cultured HeLa and neuronal cells.
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http://dx.doi.org/10.1038/s41598-018-33613-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189086PMC
October 2018

Genetic determinants of childhood and adult height associated with osteosarcoma risk.

Cancer 2018 09 12;124(18):3742-3752. Epub 2018 Oct 12.

Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, California.

Background: Although increased height has been associated with osteosarcoma risk in previous epidemiologic studies, to the authors' knowledge the relative contribution of stature during different developmental timepoints remains unclear. Furthermore, the question of how genetic determinants of height impact osteosarcoma etiology remains unexplored. Genetic variants associated with stature in previous genome-wide association studies may be biomarkers of osteosarcoma risk.

Methods: The authors tested the associations between osteosarcoma risk and polygenic scores for adult height (416 variants), childhood height (6 variants), and birth length (5 variants) in 864 osteosarcoma cases and 1879 controls of European ancestry.

Results: Each standard deviation increase in the polygenic score for adult height, corresponding to a 1.7-cm increase in stature, was found to be associated with a 1.10-fold increase in the risk of osteosarcoma (95% confidence interval [95% CI], 1.01-1.19; P =.027). Each standard deviation increase in the polygenic score for childhood height, corresponding to a 0.5-cm increase in stature, was associated with a 1.10-fold increase in the risk of osteosarcoma (95% CI, 1.01-1.20; P =.023). The polygenic score for birth length was not found to be associated with osteosarcoma risk (P =.11). When adult and childhood height scores were modeled together, they were found to be independently associated with osteosarcoma risk (P =.037 and P = .043, respectively). An expression quantitative trait locus for cartilage intermediate layer protein 2 (CILP2), rs8103992, was significantly associated with osteosarcoma risk after adjustment for multiple comparisons (odds ratio, 1.35; 95% CI, 1.16-1.56 [P = 7.93×10 and P =.034]).

Conclusions: A genetic propensity for taller adult and childhood height attainments contributed independently to osteosarcoma risk in the current study data. These results suggest that the biological pathways affecting normal bone growth may be involved in osteosarcoma etiology.
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http://dx.doi.org/10.1002/cncr.31645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214707PMC
September 2018

Ultrahigh-throughput functional profiling of microbiota communities.

Proc Natl Acad Sci U S A 2018 09 4;115(38):9551-9556. Epub 2018 Sep 4.

Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520;

Microbiome spectra serve as critical clues to elucidate the evolutionary biology pathways, potential pathologies, and even behavioral patterns of the host organisms. Furthermore, exotic sources of microbiota represent an unexplored niche to discover microbial secondary metabolites. However, establishing the bacterial functionality is complicated by an intricate web of interactions inside the microbiome. Here we apply an ultrahigh-throughput (uHT) microfluidic droplet platform for activity profiling of the entire oral microbial community of the Siberian bear to isolate strains demonstrating antimicrobial activity against Genome mining allowed us to identify antibiotic amicoumacin A (Ami) as responsible for inhibiting the growth of Proteomics and metabolomics revealed a unique mechanism of self-resistance to Ami, based on a subtle equilibrium of its deactivation and activation by kinase AmiN and phosphatase AmiO, respectively. We developed uHT quantitative single-cell analysis to estimate antibiotic efficacy toward different microbiomes and used it to determine the activity spectra of Ami toward human and Siberian bear microbiota. Thus, uHT microfluidic droplet platform activity profiling is a powerful tool for discovering antibiotics and quantifying external influences on a microbiome.
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http://dx.doi.org/10.1073/pnas.1811250115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156654PMC
September 2018

QM/MM Description of Newly Selected Catalytic Bioscavengers Against Organophosphorus Compounds Revealed Reactivation Stimulus Mediated by Histidine Residue in the Acyl-Binding Loop.

Front Pharmacol 2018 3;9:834. Epub 2018 Aug 3.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.

Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by altering its p, which in turn promotes the activation of water molecule in terms of its nucleophilicity. Observed re-protonation of catalytic serine residue at position 198 from histidine residue at position 438 recovers initial configuration of the enzyme's active center, facilitating next catalytic cycle. We therefore suggest that utilization of uHTS platform in combination with deciphering of molecular mechanisms by QM/MM calculations may significantly improve our knowledge of enzyme function, propose new strategies for enzyme design and open new horizons in generation of catalytic bioscavengers against OP poisons.
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http://dx.doi.org/10.3389/fphar.2018.00834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085465PMC
August 2018

Two HLA Class II Gene Variants Are Independently Associated with Pediatric Osteosarcoma Risk.

Cancer Epidemiol Biomarkers Prev 2018 10 23;27(10):1151-1158. Epub 2018 Jul 23.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.

The genetic etiology of osteosarcoma remains poorly understood despite the publication of a genome-wide association study. Association between HLA genetic variants and risk of several cancers has been observed, but HLA variation is not well captured by standard SNP arrays. We genotyped 207 Californian pediatric osteosarcoma cases and 696 controls of European ancestry using a custom genome-wide array supplemented with approximately 6,000 additional probes across the MHC region. We subsequently imputed 4-digit classical HLA alleles using a reference panel of 5,225 individuals who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for ancestry-informative principal components, and top associations from the discovery analysis underwent replication in an independent dataset of 657 cases and 1,183 controls. Three highly correlated HLA class II variants ( = 0.33-0.98) were associated with osteosarcoma risk in discovery analyses, including (OR = 0.52; = 3.2 × 10), (OR = 0.74; = 0.031), and (OR = 0.51; = 2.7 × 10). Similar associations were observed in the replication data ( = 0.011-0.037). Meta-analysis of the two datasets identified as the most significantly associated variant (OR = 0.62; = 1.5 × 10), reaching Bonferroni-corrected statistical significance. The meta-analysis also revealed a second significant independent signal at (OR = 1.33, = 1.2 × 10), and a third suggestive association at (OR = 0.73, = 6.4 × 10). Multiple independent HLA class II alleles may influence osteosarcoma risk. Additional work is needed to extend our observations to other patient populations and to clarify the potential causal mechanisms underlying these associations. Understanding immunologic contributions to the etiology of osteosarcoma may inform rational therapeutic targets. .
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170682PMC
October 2018

BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.

Int J Cancer 2018 12 3;143(11):2647-2658. Epub 2018 Oct 3.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.

Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (p < 10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (p = 2.1 x 10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10 ) and p300 (p = 1.55 x 10 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (p = 1.3 x 10 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.
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http://dx.doi.org/10.1002/ijc.31622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235695PMC
December 2018

Genome-wide association analysis identifies a meningioma risk locus at 11p15.5.

Neuro Oncol 2018 10;20(11):1485-1493

Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

Background: Meningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31.

Methods: To identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls.

Results: We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges.

Conclusions: This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma.
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http://dx.doi.org/10.1093/neuonc/noy077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176799PMC
October 2018

GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21.

Nat Commun 2018 01 18;9(1):286. Epub 2018 Jan 18.

Department of Chronic Diseases Epidemiology, School of Public Health, Yale University, 60 College Street, New Haven, CT, 06520, USA.

Childhood acute lymphoblastic leukemia (ALL) (age 0-14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children's Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near IKZF3/ZPBP2/GSDMB/ORMDL3, a locus encompassing a transcription factor important for lymphocyte development (IKZF3), and at an 8q24 region known for structural contacts with the MYC oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways.
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http://dx.doi.org/10.1038/s41467-017-02596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773513PMC
January 2018

Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas.

Neuro Oncol 2018 04;20(5):632-641

Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

Background: Rare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution.

Methods: In this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions.

Results: One patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second.

Conclusions: Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.
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http://dx.doi.org/10.1093/neuonc/nox205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892142PMC
April 2018

Comprehensive Analysis of Hypermutation in Human Cancer.

Cell 2017 Nov 19;171(5):1042-1056.e10. Epub 2017 Oct 19.

Department of Pediatric Hematology-Oncology, Sheba Medical Center, Tel Hashomer, Israel.

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.
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http://dx.doi.org/10.1016/j.cell.2017.09.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849393PMC
November 2017