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Bivariate Poisson models with varying offsets: an application to the paired mitochondrial DNA dataset.
Su PF, Mau YL, Guo Y, Li CI, Liu Q, Boice JD, Shyr Y
(2017) Stat Appl Genet Mol Biol 16: 47-58
MeSH Terms: Antineoplastic Agents, Base Sequence, Cancer Survivors, Computer Simulation, DNA, Mitochondrial, Databases, Nucleic Acid, Genome, Mitochondrial, Humans, Models, Biological, Mutation Rate, Regression Analysis
Show Abstract · Added April 18, 2017
To assess the effect of chemotherapy on mitochondrial genome mutations in cancer survivors and their offspring, a study sequenced the full mitochondrial genome and determined the mitochondrial DNA heteroplasmic (mtDNA) mutation rate. To build a model for counts of heteroplasmic mutations in mothers and their offspring, bivariate Poisson regression was used to examine the relationship between mutation count and clinical information while accounting for the paired correlation. However, if the sequencing depth is not adequate, a limited fraction of the mtDNA will be available for variant calling. The classical bivariate Poisson regression model treats the offset term as equal within pairs; thus, it cannot be applied directly. In this research, we propose an extended bivariate Poisson regression model that has a more general offset term to adjust the length of the accessible genome for each observation. We evaluate the performance of the proposed method with comprehensive simulations, and the results show that the regression model provides unbiased parameter estimations. The use of the model is also demonstrated using the paired mtDNA dataset.
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11 MeSH Terms
DNA polymerases κ and ζ cooperatively perform mutagenic translesion synthesis of the C8-2'-deoxyguanosine adduct of the dietary mutagen IQ in human cells.
Bose A, Pande P, Jasti VP, Millsap AD, Hawkins EK, Rizzo CJ, Basu AK
(2015) Nucleic Acids Res 43: 8340-51
MeSH Terms: DNA, DNA Adducts, DNA-Directed DNA Polymerase, Deoxyguanosine, HEK293 Cells, Humans, Mutagens, Mutation Rate, Quinolines
Show Abstract · Added January 7, 2016
The roles of translesion synthesis (TLS) DNA polymerases in bypassing the C8-2'-deoxyguanosine adduct (dG-C8-IQ) formed by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a highly mutagenic and carcinogenic heterocyclic amine found in cooked meats, were investigated. Three plasmid vectors containing the dG-C8-IQ adduct at the G1-, G2- or G3-positions of the NarI site (5'-G1G2CG3CC-3') were replicated in HEK293T cells. Fifty percent of the progeny from the G3 construct were mutants, largely G→T, compared to 18% and 24% from the G1 and G2 constructs, respectively. Mutation frequency (MF) of dG-C8-IQ was reduced by 38-67% upon siRNA knockdown of pol κ, whereas it was increased by 10-24% in pol η knockdown cells. When pol κ and pol ζ were simultaneously knocked down, MF of the G1 and G3 constructs was reduced from 18% and 50%, respectively, to <3%, whereas it was reduced from 24% to <1% in the G2 construct. In vitro TLS using yeast pol ζ showed that it can extend G3*:A pair more efficiently than G3*:C pair, but it is inefficient at nucleotide incorporation opposite dG-C8-IQ. We conclude that pol κ and pol ζ cooperatively carry out the majority of the error-prone TLS of dG-C8-IQ, whereas pol η is involved primarily in its error-free bypass.
© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
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9 MeSH Terms
Tissue-specific expressed antibody variable gene repertoires.
Briney BS, Willis JR, Finn JA, McKinney BA, Crowe JE
(2014) PLoS One 9: e100839
MeSH Terms: Adolescent, Adult, Antibodies, Bone Marrow, Cluster Analysis, Complementarity Determining Regions, DNA, Demography, Gene Expression Regulation, Germ Cells, High-Throughput Nucleotide Sequencing, Humans, Immunoglobulin Variable Region, Lymphoid Tissue, Middle Aged, Mucous Membrane, Mutation, Mutation Rate, Organ Specificity, RNA, Somatic Hypermutation, Immunoglobulin, V(D)J Recombination, Young Adult
Show Abstract · Added February 2, 2015
Recent developments in genetic technologies allow deep analysis of the sequence diversity of immune repertoires, but little work has been reported on the architecture of immune repertoires in mucosal tissues. Antibodies are the key to prevention of infections at the mucosal surface, but it is currently unclear whether the B cell repertoire at mucosal surfaces reflects the dominant antibodies found in the systemic compartment or whether mucosal tissues harbor unique repertoires. We examined the expressed antibody variable gene repertoires from 10 different human tissues using RNA samples derived from a large number of individuals. The results revealed that mucosal tissues such as stomach, intestine and lung possess unique antibody gene repertoires that differed substantially from those found in lymphoid tissues or peripheral blood. Mutation frequency analysis of mucosal tissue repertoires revealed that they were highly mutated, with little evidence for the presence of naïve B cells, in contrast to blood. Mucosal tissue repertoires possessed longer heavy chain complementarity determining region 3 loops than lymphoid tissue repertoires. We also noted a large increase in frequency of both insertions and deletions in the small intestine antibody repertoire. These data suggest that mucosal immune repertoires are distinct in many ways from the systemic compartment.
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23 MeSH Terms
In vivo roles of conjugation with glutathione and O6-alkylguanine DNA-alkyltransferase in the mutagenicity of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane in mice.
Cho SH, Guengerich FP
(2013) Chem Res Toxicol 26: 1765-74
MeSH Terms: Animals, Butadienes, Buthionine Sulfoximine, Chromatography, High Pressure Liquid, DNA Adducts, DNA Mutational Analysis, Epoxy Compounds, Ethylene Dibromide, Glutathione, Glutathione Transferase, Guanine, Liver, Male, Mice, Mice, Transgenic, Mutagenicity Tests, Mutation, Mutation Rate, O(6)-Methylguanine-DNA Methyltransferase, Spectrometry, Mass, Electrospray Ionization
Show Abstract · Added March 7, 2014
Several studies with bacteria and in vitro mammalian systems have provided evidence of the roles of two thiol-based conjugation systems, glutathione (GSH) transferase and O(6)-alkylguanine DNA-alkyltransferase (AGT), in the bioactivation of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane (DEB), the latter an oxidation product of 1,3-butadiene. The in vivo relevance of these conjugation reactions to biological activity in mammals has not been addressed, particularly with DEB. In this work, we used transgenic Big Blue mice, utilizing the cII gene, to examine the effects of manipulation of conjugation pathways on liver mutations arising from dibromoethane and DEB in vivo. Treatment of the mice with butathionine sulfoxime (BSO) prior to dibromoethane lowered hepatic GSH levels, dibromoethane-GSH DNA adduct levels (N(7)-guanyl), and the cII mutation frequency. Administration of O(6)-benzylguanine (O(6)-BzGua), an inhibitor of AGT, did not change the mutation frequency. Depletion of GSH (BSO) and AGT (O(6)-BzGua) lowered the mutation frequency induced by DEB, and BSO lowered the levels of GSH-DEB N(7)-guanyl and N(6)-adenyl DNA adducts. Our results provide evidence that the GSH conjugation pathway is a major in vivo factor in dibromoethane genotoxicity; both GSH conjugation and AGT conjugation are major factors in the genotoxicity of DEB. The latter findings are considered to be relevant to the carcinogenicity of 1,3-butadiene.
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20 MeSH Terms
Pif1 family helicases suppress genome instability at G-quadruplex motifs.
Paeschke K, Bochman ML, Garcia PD, Cejka P, Friedman KL, Kowalczykowski SC, Zakian VA
(2013) Nature 497: 458-62
MeSH Terms: Base Sequence, Conserved Sequence, DNA Damage, DNA Helicases, Epigenesis, Genetic, Evolution, Molecular, G-Quadruplexes, Gene Silencing, Genetic Complementation Test, Genomic Instability, Humans, Molecular Sequence Data, Mutation Rate, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomere Homeostasis
Show Abstract · Added March 7, 2014
The Saccharomyces cerevisiae Pif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteria to humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1 helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolution suppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generated in the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressed in yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening.
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16 MeSH Terms
Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma.
Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL, Kela I, Hopmans ES, Myklebust JH, Ji H, Plevritis SK, Levy R, Alizadeh AA
(2013) Blood 121: 1604-11
MeSH Terms: Clonal Evolution, Clone Cells, DNA, Neoplasm, Disease Progression, Exome, Gene Frequency, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Immunophenotyping, Lymphoma, Follicular, Mutation, Mutation Rate, Polymerase Chain Reaction, Recurrence
Show Abstract · Added February 15, 2013
Follicular lymphoma (FL) is currently incurable using conventional chemotherapy or immunotherapy regimes, compelling new strategies. Advances in high-throughput sequencing technologies that can reveal oncogenic pathways have stimulated interest in tailoring therapies toward actionable somatic mutations. However, for mutation-directed therapies to be most effective, the mutations must be uniformly present in evolved tumor cells as well as in the self-renewing tumor-cell precursors. Here, we show striking intratumoral clonal diversity within FL tumors in the representation of mutations in the majority of genes as revealed by whole exome sequencing of subpopulations. This diversity captures a clonal hierarchy, resolved using immunoglobulin somatic mutations and IGH-BCL2 translocations as a frame of reference and by comparing diagnosis and relapse tumor pairs, allowing us to distinguish early versus late genetic eventsduring lymphomagenesis. We provide evidence that IGH-BCL2 translocations and CREBBP mutations are early events, whereas MLL2 and TNFRSF14 mutations probably represent late events during disease evolution. These observations provide insight into which of the genetic lesions represent suitable candidates for targeted therapies.
1 Communities
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15 MeSH Terms
Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing.
Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A, Sougnez C, Auclair D, Lawrence MS, Stojanov P, Cibulskis K, Choi K, de Waal L, Sharifnia T, Brooks A, Greulich H, Banerji S, Zander T, Seidel D, Leenders F, Ansén S, Ludwig C, Engel-Riedel W, Stoelben E, Wolf J, Goparju C, Thompson K, Winckler W, Kwiatkowski D, Johnson BE, Jänne PA, Miller VA, Pao W, Travis WD, Pass HI, Gabriel SB, Lander ES, Thomas RK, Garraway LA, Getz G, Meyerson M
(2012) Cell 150: 1107-20
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Cohort Studies, Exome, Female, Genes, Neoplasm, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Mutation Rate
Show Abstract · Added September 3, 2013
Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.
Copyright © 2012 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Personalized pathway enrichment map of putative cancer genes from next generation sequencing data.
Jia P, Zhao Z
(2012) PLoS One 7: e37595
MeSH Terms: Genes, Neoplasm, Genomics, High-Throughput Nucleotide Sequencing, Humans, Mutation Rate, Sequence Analysis, DNA
Show Abstract · Added March 5, 2014
BACKGROUND - Pathway analysis of a set of genes represents an important area in large-scale omic data analysis. However, the application of traditional pathway enrichment methods to next-generation sequencing (NGS) data is prone to several potential biases, including genomic/genetic factors (e.g., the particular disease and gene length) and environmental factors (e.g., personal life-style and frequency and dosage of exposure to mutagens). Therefore, novel methods are urgently needed for these new data types, especially for individual-specific genome data.
METHODOLOGY - In this study, we proposed a novel method for the pathway analysis of NGS mutation data by explicitly taking into account the gene-wise mutation rate. We estimated the gene-wise mutation rate based on the individual-specific background mutation rate along with the gene length. Taking the mutation rate as a weight for each gene, our weighted resampling strategy builds the null distribution for each pathway while matching the gene length patterns. The empirical P value obtained then provides an adjusted statistical evaluation.
PRINCIPAL FINDINGS/CONCLUSIONS - We demonstrated our weighted resampling method to a lung adenocarcinomas dataset and a glioblastoma dataset, and compared it to other widely applied methods. By explicitly adjusting gene-length, the weighted resampling method performs as well as the standard methods for significant pathways with strong evidence. Importantly, our method could effectively reject many marginally significant pathways detected by standard methods, including several long-gene-based, cancer-unrelated pathways. We further demonstrated that by reducing such biases, pathway crosstalk for each individual and pathway co-mutation map across multiple individuals can be objectively explored and evaluated. This method performs pathway analysis in a sample-centered fashion, and provides an alternative way for accurate analysis of cancer-personalized genomes. It can be extended to other types of genomic data (genotyping and methylation) that have similar bias problems.
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6 MeSH Terms
The use of next generation sequencing technology to study the effect of radiation therapy on mitochondrial DNA mutation.
Guo Y, Cai Q, Samuels DC, Ye F, Long J, Li CI, Winther JF, Tawn EJ, Stovall M, Lähteenmäki P, Malila N, Levy S, Shaffer C, Shyr Y, Shu XO, Boice JD
(2012) Mutat Res 744: 154-60
MeSH Terms: Adolescent, Child, Child, Preschool, DNA, Mitochondrial, Female, Humans, Infant, Mutation Rate, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Pregnancy, Prenatal Exposure Delayed Effects, Radiation Injuries, Sequence Analysis, DNA, Survivors, Young Adult
Show Abstract · Added December 12, 2013
The human mitochondrial genome has an exclusively maternal mode of inheritance. Mitochondrial DNA (mtDNA) is particularly vulnerable to environmental insults due in part to an underdeveloped DNA repair system, limited to base excision and homologous recombination repair. Radiation exposure to the ovaries may cause mtDNA mutations in oocytes, which may in turn be transmitted to offspring. We hypothesized that the children of female cancer survivors who received radiation therapy may have an increased rate of mtDNA heteroplasmy mutations, which conceivably could increase their risk of developing cancer and other diseases. We evaluated 44 DNA blood samples from 17 Danish and 1 Finnish families (18 mothers and 26 children). All mothers had been treated for cancer as children and radiation doses to their ovaries were determined based on medical records and computational models. DNA samples were sequenced for the entire mitochondrial genome using the Illumina GAII system. Mother's age at sample collection was positively correlated with mtDNA heteroplasmy mutations. There was evidence of heteroplasmy inheritance in that 9 of the 18 families had at least one child who inherited at least one heteroplasmy site from his or her mother. No significant difference in single nucleotide polymorphisms between mother and offspring, however, was observed. Radiation therapy dose to ovaries also was not significantly associated with the heteroplasmy mutation rate among mothers and children. No evidence was found that radiotherapy for pediatric cancer is associated with the mitochondrial genome mutation rate in female cancer survivors and their children.
Copyright © 2012 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Lung adenocarcinomas with HER2-activating mutations are associated with distinct clinical features and HER2/EGFR copy number gains.
Li C, Sun Y, Fang R, Han X, Luo X, Wang R, Pan Y, Hu H, Zhang Y, Pao W, Shen L, Ji H, Chen H
(2012) J Thorac Oncol 7: 85-9
MeSH Terms: Adenocarcinoma, Aged, DNA Mutational Analysis, ErbB Receptors, Female, Gene Amplification, Gene Dosage, Humans, Lung Neoplasms, Male, Middle Aged, Mutation Rate, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Receptor, ErbB-2, Smoking, ras Proteins
Show Abstract · Added September 3, 2013
INTRODUCTION - A fraction of lung adenocarcinomas harbor activating mutations in the HER2 kinase domain. HER2-targeted therapies have shown minimal benefit in molecularly unselected patients. We investigated clinical and potential molecular factors associated with HER2-mutant lung adenocarcinoma.
METHODS - A total of 224 lung adenocarcinoma samples were examined for activating mutations in epidermal growth factor receptor (EGFR; exons 18-22), V-Ki-ras2 Kirsten rat sarcoma (KRAS; exons 2 and 3), and HER2 (exons 18-21) by direct sequencing. Gene copy number and protein expression of both EGFR and HER2 were further explored in samples harboring HER2 mutations using fluorescence in situ hybridization and immunohistochemistry, respectively.
RESULTS - The mutation rates of EGFR, KRAS, HER2 were 63.39% (142/224), 4.46% (10/224), and 3.57% (8/224), respectively. All mutations were mutually exclusive. All eight HER2 mutations occurred in never smokers and seven were in women. The HER2 mutation rate in samples without EGFR and KRAS mutations was 11.11% (8/72). Seven of eight HER2-mutated tumors showed HER2 copy number gains (CNGs) and five showed EGFR CNGs. All of the HER2-mutated samples showed either HER2 or EGFR CNGs. Gene amplification of HER2 and EGFR was mutually exclusive in HER2-mutated samples.
CONCLUSION - HER2 mutations in lung adenocarcinoma predominantly occurred in women and never smokers. Most HER2-mutated tumors showed HER2 CNGs. As all of the samples with HER2 mutation showed either HER2 or EGFR CNGs, these patients could potentially benefit from novel EGFR/HER2 dual or pan-erythroblastic leukemia viral oncogene homolog tyrosine kinase inhibitors.
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17 MeSH Terms