LIVIVO - Search results -

Search results

Result 1 - 10 of total 13

Search options

Article: Adopting Duplex Sequencing™ Technology for Genetic Toxicity Testing: A Proof-of-Concept Mutagenesis Experiment with N-Ethyl-N-Nitrosourea (ENU)-Exposed Rats.

Smith-Roe, Stephanie L / Hobbs, Cheryl A / Hull, Victoria / Auman, J Todd / Recio, Leslie / Streicker, Michael A / Rivas, Miriam V / Pratt, Gabriel A / Lo, Fang Yin / Higgins, Jacob E / Schmidt, Elizabeth K / Williams, Lindsey N / Nachmanson, Daniela / Valentine, Charles C / Salk, Jesse J / Witt, Kristine L

bioRxiv : the preprint server for biology

2023

Abstract: Duplex sequencing (DuplexSeq) is an error-corrected next-generation sequencing (ecNGS) method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors by comparing grouped ... ...

Abstract	Duplex sequencing (DuplexSeq) is an error-corrected next-generation sequencing (ecNGS) method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors by comparing grouped strand sequencing reads. The resulting background of less than one artifactual mutation per 10 Highlights: DuplexSeq is an ultra-accurate NGS technology that directly quantifies mutationsENU-dependent mutagenesis was detected 24 h post-exposure in proliferative tissuesMultiple tissues exhibited the canonical ENU mutation spectrum 7 d after exposureResults obtained with DuplexSeq were highly concordant between laboratoriesThe Rat-50 Mutagenesis Assay is promising for applications in genetic toxicology.
Language	English
Publishing date	2023-05-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.08.539833
Database	MEDical Literature Analysis and Retrieval System OnLINE

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾

Article ; Online: Adopting duplex sequencing technology for genetic toxicity testing: A proof-of-concept mutagenesis experiment with N-ethyl-N-nitrosourea (ENU)-exposed rats.

Smith-Roe, Stephanie L / Hobbs, Cheryl A / Hull, Victoria / Todd Auman, J / Recio, Leslie / Streicker, Michael A / Rivas, Miriam V / Pratt, Gabriel A / Lo, Fang Yin / Higgins, Jacob E / Schmidt, Elizabeth K / Williams, Lindsey N / Nachmanson, Daniela / Valentine Iii, Charles C / Salk, Jesse J / Witt, Kristine L

Mutation research. Genetic toxicology and environmental mutagenesis

2023 Volume 891, Page(s) 503669

Abstract: Duplex sequencing (DS) is an error-corrected next-generation sequencing method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors in consensus sequences. The resulting ... ...

Abstract	Duplex sequencing (DS) is an error-corrected next-generation sequencing method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors in consensus sequences. The resulting background of less than one artifactual mutation per 10
MeSH term(s)	Rats ; Male ; Animals ; Ethylnitrosourea/toxicity ; Reproducibility of Results ; Rats, Sprague-Dawley ; Mutagenesis ; Mutation ; Nitrosourea Compounds ; Mutagens/toxicity
Chemical Substances	Ethylnitrosourea (P8M1T4190R) ; Nitrosourea Compounds ; Mutagens
Language	English
Publishing date	2023-08-03
Publishing country	Netherlands
Document type	Journal Article
ISSN	1879-3592
ISSN (online)	1879-3592
DOI	10.1016/j.mrgentox.2023.503669
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾
- Full text online
- Order with fees

Article ; Online: Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing.

Valentine, Charles C / Young, Robert R / Fielden, Mark R / Kulkarni, Rohan / Williams, Lindsey N / Li, Tan / Minocherhomji, Sheroy / Salk, Jesse J

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 52, Page(s) 33414–33425

Abstract: The ability to accurately measure mutations is critical for basic research and identifying potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems that ... ...

Abstract	The ability to accurately measure mutations is critical for basic research and identifying potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems that are low-throughput, expensive, prolonged, and do not fully represent other species such as humans. Next-generation sequencing (NGS) is a conceptually attractive alternative for detecting mutations in the DNA of any organism; however, the limit of resolution for standard NGS is poor. Technical error rates (∼1 × 10
MeSH term(s)	Animals ; Carcinogenesis/genetics ; Carcinogens/toxicity ; Cluster Analysis ; DNA/genetics ; Genes, ras ; Genetic Loci ; Genome ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Mice, Transgenic ; Mutagenesis/genetics ; Mutation/genetics ; Neoplasms/genetics ; Oncogenes ; Phenotype ; Transcription, Genetic
Chemical Substances	Carcinogens ; DNA (9007-49-2)
Language	English
Publishing date	2020-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2013724117
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1148: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Emergence of DNA polymerase ε antimutators that escape error-induced extinction in yeast.

Williams, Lindsey N / Herr, Alan J / Preston, Bradley D

Genetics

2013 Volume 193, Issue 3, Page(s) 751–770

Abstract: DNA polymerases (Pols) ε and δ perform the bulk of yeast leading- and lagging-strand DNA synthesis. Both Pols possess intrinsic proofreading exonucleases that edit errors during polymerization. Rare errors that elude proofreading are extended into duplex ...

Abstract	DNA polymerases (Pols) ε and δ perform the bulk of yeast leading- and lagging-strand DNA synthesis. Both Pols possess intrinsic proofreading exonucleases that edit errors during polymerization. Rare errors that elude proofreading are extended into duplex DNA and excised by the mismatch repair (MMR) system. Strains that lack Pol proofreading or MMR exhibit a 10- to 100-fold increase in spontaneous mutation rate (mutator phenotype), and inactivation of both Pol δ proofreading (pol3-01) and MMR is lethal due to replication error-induced extinction (EEX). It is unclear whether a similar synthetic lethal relationship exists between defects in Pol ε proofreading (pol2-4) and MMR. Using a plasmid-shuffling strategy in haploid Saccharomyces cerevisiae, we observed synthetic lethality of pol2-4 with alleles that completely abrogate MMR (msh2Δ, mlh1Δ, msh3Δ msh6Δ, or pms1Δ mlh3Δ) but not with partial MMR loss (msh3Δ, msh6Δ, pms1Δ, or mlh3Δ), indicating that high levels of unrepaired Pol ε errors drive extinction. However, variants that escape this error-induced extinction (eex mutants) frequently emerged. Five percent of pol2-4 msh2Δ eex mutants encoded second-site changes in Pol ε that reduced the pol2-4 mutator phenotype between 3- and 23-fold. The remaining eex alleles were extragenic to pol2-4. The locations of antimutator amino-acid changes in Pol ε and their effects on mutation spectra suggest multiple mechanisms of mutator suppression. Our data indicate that unrepaired leading- and lagging-strand polymerase errors drive extinction within a few cell divisions and suggest that there are polymerase-specific pathways of mutator suppression. The prevalence of suppressors extragenic to the Pol ε gene suggests that factors in addition to proofreading and MMR influence leading-strand DNA replication fidelity.
MeSH term(s)	Amino Acid Sequence ; DNA Mismatch Repair/genetics ; DNA Polymerase II/chemistry ; DNA Polymerase II/genetics ; DNA Polymerase II/metabolism ; DNA Replication/genetics ; Molecular Sequence Data ; Mutation Rate ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	Saccharomyces cerevisiae Proteins ; DNA Polymerase II (EC 2.7.7.7)
Language	English
Publishing date	2013-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1534/genetics.112.146910
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.B 767: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Direct Quantification of in vivo Mutagenesis and Carcinogenesis Using Duplex Sequencing

Valentine, Charles C. / Young, Robert R. / Fielden, Mark R. / Kulkarni, Rohan / Williams, Lindsey N. / Li, Tan / Minocherhomji, Sheroy / Salk, Jesse J.

bioRxiv

Abstract: The ability to accurately measure mutations is critical for basic research and identification of potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems ...

Abstract	The ability to accurately measure mutations is critical for basic research and identification of potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems that are low-throughput, expensive, prolonged, and don’t fully represent other species such as humans. Next generation sequencing (NGS) is a conceptually attractive alternative for mutation detection in the DNA of any organism, however, the limit of resolution for standard NGS is poor. Technical error rates (~1×10−3) of NGS obscure the true abundance of somatic mutations, which can exist at pernucleotide frequencies ≤1×10−7. Using Duplex Sequencing, an extremely accurate error-corrected NGS (ecNGS) technology, we were able to detect mutations induced by 3 carcinogens in 5 tissues of 2 strains of mice within 31 days following exposure. We observed a strong correlation between mutation induction measured by Duplex Sequencing and the gold-standard transgenic rodent mutation assay. We identified exposure-specific mutation spectra of each compound through trinucleotide patterns of base substitution. We observed variation in mutation susceptibility by genomic region, as well as by DNA strand. We also identified the primordial signs of carcinogenesis in a cancer-predisposed strain of mice, as evidenced by clonal expansions of cells carrying an activated oncogene, less than a month after carcinogen exposure. These findings demonstrate that ecNGS is a powerful method for sensitively detecting and characterizing mutagenesis and the early clonal evolutionary hallmarks of carcinogenesis. Duplex Sequencing can be broadly applied to chemical safety testing, basic mutational research, and related clinical uses. SIGNIFICANCE STATEMENT Error-corrected next generation sequencing (ecNGS) can be used to rapidly detect and quantify the in vivo mutagenic impact of environmental exposures or endogenous processes in any tissue, from any species, at any genomic location. The greater speed, higher scalability, richer data outputs, as well as cross-species and cross-locus applicability of ecNGS compared to existing methods make it a powerful new tool for mutational research, regulatory safety testing, and emerging clinical applications.
Keywords	covid19
Publisher	BioRxiv
Document type	Article ; Online
DOI	10.1101/2020.06.28.176685
Database	COVID19

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾

Article ; Online: Antimutator variants of DNA polymerases.

Herr, Alan J / Williams, Lindsey N / Preston, Bradley D

Critical reviews in biochemistry and molecular biology

2011 Volume 46, Issue 6, Page(s) 548–570

Abstract: Evolution balances DNA replication speed and accuracy to optimize replicative fitness and genetic stability. There is no selective pressure to improve DNA replication fidelity beyond the background mutation rate from other sources, such as DNA damage. ... ...

Abstract	Evolution balances DNA replication speed and accuracy to optimize replicative fitness and genetic stability. There is no selective pressure to improve DNA replication fidelity beyond the background mutation rate from other sources, such as DNA damage. However, DNA polymerases remain amenable to amino acid substitutions that lower intrinsic error rates. Here, we review these 'antimutagenic' changes in DNA polymerases and discuss what they reveal about mechanisms of replication fidelity. Pioneering studies with bacteriophage T4 DNA polymerase (T4 Pol) established the paradigm that antimutator amino acid substitutions reduce replication errors by increasing proofreading efficiency at the expense of polymerase processivity. The discoveries of antimutator substitutions in proofreading-deficient 'mutator' derivatives of bacterial Pols I and III and yeast Pol δ suggest there must be additional antimutagenic mechanisms. Remarkably, many of the affected amino acid positions from Pol I, Pol III, and Pol δ are similar to the original T4 Pol substitutions. The locations of antimutator substitutions within DNA polymerase structures suggest that they may increase nucleotide selectivity and/or promote dissociation of primer termini from polymerases poised for misincorporation, leading to expulsion of incorrect nucleotides. If misincorporation occurs, enhanced primer dissociation from polymerase domains may improve proofreading in cis by an intrinsic exonuclease or in trans by alternate cellular proofreading activities. Together, these studies reveal that natural selection can readily restore replication error rates to sustainable levels following an adaptive mutator phenotype.
MeSH term(s)	Animals ; DNA Mismatch Repair ; DNA Replication ; DNA-Directed DNA Polymerase/chemistry ; DNA-Directed DNA Polymerase/genetics ; Genetic Variation ; Humans ; Models, Molecular ; Mutation ; Protein Conformation
Chemical Substances	DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2011-10-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1000977-2
ISSN	1549-7798 ; 1381-3455 ; 1040-9238
ISSN (online)	1549-7798
ISSN	1381-3455 ; 1040-9238
DOI	10.3109/10409238.2011.620941
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1024: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Genetic toxicity testing using human in vitro organotypic airway cultures: Assessing DNA damage with the CometChip and mutagenesis by Duplex Sequencing.

Wang, Yiying / Mittelstaedt, Roberta A / Wynne, Rebecca / Chen, Ying / Cao, Xuefei / Muskhelishvili, Levan / Davis, Kelly / Robison, Timothy W / Sun, Wei / Schmidt, Elizabeth K / Smith, Thomas H / Norgaard, Zachary K / Valentine, Charles C / Yaplee, Jeffry / Williams, Lindsey N / Salk, Jesse J / Heflich, Robert H

Environmental and molecular mutagenesis

2021 Volume 62, Issue 5, Page(s) 306–318

Abstract: The organotypic human air-liquid-interface (ALI) airway tissue model has been used as an in vitro cell culture system for evaluating the toxicity of inhaled substances. ALI airway cultures are highly differentiated, which has made it challenging to ... ...

Abstract	The organotypic human air-liquid-interface (ALI) airway tissue model has been used as an in vitro cell culture system for evaluating the toxicity of inhaled substances. ALI airway cultures are highly differentiated, which has made it challenging to evaluate genetic toxicology endpoints. In the current study, we assayed DNA damage with the high-throughput CometChip assay and quantified mutagenesis with Duplex Sequencing, an error-corrected next-generation sequencing method capable of detecting a single mutation per 10
MeSH term(s)	DNA Damage ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Ethyl Methanesulfonate/adverse effects ; Humans ; Mutagenesis ; Mutagenicity Tests/methods ; Mutagens/adverse effects ; Mutation ; Respiratory System/drug effects ; Respiratory System/metabolism ; Respiratory System/pathology
Chemical Substances	Mutagens ; Ethyl Methanesulfonate (9H154DI0UP)
Language	English
Publishing date	2021-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	639145-x
ISSN	1098-2280 ; 0893-6692
ISSN (online)	1098-2280
ISSN	0893-6692
DOI	10.1002/em.22444
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.B 2404: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article ; Online: dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants.

Williams, Lindsey N / Marjavaara, Lisette / Knowels, Gary M / Schultz, Eric M / Fox, Edward J / Chabes, Andrei / Herr, Alan J

Proceedings of the National Academy of Sciences of the United States of America

2015 Volume 112, Issue 19, Page(s) E2457–66

Abstract: Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that ... ...

Abstract	Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.
MeSH term(s)	Alleles ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/therapeutic use ; Cell Cycle ; DNA Mutational Analysis ; DNA Replication ; DNA-Directed DNA Polymerase/genetics ; Genetic Variation ; Humans ; Mutagenesis ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Nucleotides/chemistry ; Phenotype ; Phosphates/chemistry ; Plasmids/metabolism ; S Phase ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism
Chemical Substances	Antineoplastic Agents ; Nucleotides ; Phosphates ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; Rad30 protein (EC 2.7.7.7)
Language	English
Publishing date	2015-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1422948112
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1148: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Ultra-Sensitive TP53 Sequencing for Cancer Detection Reveals Progressive Clonal Selection in Normal Tissue over a Century of Human Lifespan.

Salk, Jesse J / Loubet-Senear, Kaitlyn / Maritschnegg, Elisabeth / Valentine, Charles C / Williams, Lindsey N / Higgins, Jacob E / Horvat, Reinhard / Vanderstichele, Adriaan / Nachmanson, Daniela / Baker, Kathryn T / Emond, Mary J / Loter, Emily / Tretiakova, Maria / Soussi, Thierry / Loeb, Lawrence A / Zeillinger, Robert / Speiser, Paul / Risques, Rosa Ana

Cell reports

2019 Volume 28, Issue 1, Page(s) 132–144.e3

Abstract: High-accuracy next-generation DNA sequencing promises a paradigm shift in early cancer detection by enabling the identification of mutant cancer molecules in minimally invasive body fluid samples. We demonstrate 80% sensitivity for ovarian cancer ... ...

Abstract	High-accuracy next-generation DNA sequencing promises a paradigm shift in early cancer detection by enabling the identification of mutant cancer molecules in minimally invasive body fluid samples. We demonstrate 80% sensitivity for ovarian cancer detection using ultra-accurate Duplex Sequencing to identify TP53 mutations in uterine lavage. However, in addition to tumor DNA, we also detect low-frequency TP53 mutations in nearly all lavages from women with and without cancer. These mutations increase with age and share the selection traits of clonal TP53 mutations commonly found in human tumors. We show that low-frequency TP53 mutations exist in multiple healthy tissues, from newborn to centenarian, and progressively increase in abundance and pathogenicity with older age across tissue types. Our results illustrate that subclonal cancer evolutionary processes are a ubiquitous part of normal human aging, and great care must be taken to distinguish tumor-derived from age-associated mutations in high-sensitivity clinical cancer diagnostics.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aging/genetics ; Cell-Free Nucleic Acids/genetics ; Clonal Evolution/genetics ; DNA, Neoplasm/genetics ; Databases, Genetic ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Infant, Newborn ; Middle Aged ; Mutation ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Selection, Genetic ; Sequence Analysis, DNA ; Tumor Suppressor Protein p53/genetics ; Uterus/metabolism
Chemical Substances	Cell-Free Nucleic Acids ; DNA, Neoplasm ; TP53 protein, human ; Tumor Suppressor Protein p53
Language	English
Publishing date	2019-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.05.109
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL.

Blood cancer journal

2020 Volume 10, Issue 5, Page(s) 61

Abstract: Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4-10 of ABL1 on bone marrow or peripheral blood samples from 63 ... ...

Abstract	Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4-10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%-3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Drug Resistance, Neoplasm ; Female ; Fusion Proteins, bcr-abl/genetics ; Humans ; Male ; Middle Aged ; Mutation/drug effects ; Philadelphia Chromosome/drug effects ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-abl/chemistry ; Proto-Oncogene Proteins c-abl/genetics ; Young Adult
Chemical Substances	Protein Kinase Inhibitors ; ABL1 protein, human (EC 2.7.10.2) ; Fusion Proteins, bcr-abl (EC 2.7.10.2) ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2)
Language	English
Publishing date	2020-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-020-0329-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

To top

More links

Kategorien

Inter-library loan at ZB MED

Full text online

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito