Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling
Identifieur interne : 009A34 ( Main/Exploration ); précédent : 009A33; suivant : 009A35Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling
Auteurs : Nic Waddell [Australie] ; Jyoti Jonnalagadda [Australie] ; Anna Marsh [Australie] ; Scott Grist [Australie] ; Mark Jenkins [Australie] ; Karen Hobson [Australie] ; Malcolm Taylor [Royaume-Uni] ; Geoff J. Lindeman [Australie] ; Sean V. Tavtigian [France] ; Graeme Suthers [Australie] ; David Goldgar [États-Unis] ; Peter J. Oefner [Allemagne] ; Darrin Taylor [Australie] ; Sean Grimmond [Australie] ; Kum Kum Khanna [Australie] ; Georgia Chenevix-Trench [Australie]Source :
- Genes, Chromosomes and Cancer [ 1045-2257 ] ; 2006-12.
Descripteurs français
- Wicri :
- topic : Cancer.
English descriptors
- KwdEn :
- Aberration, Array experiment, Assay, Ataxia, Ataxia telangiectasia, Breast, Breast cancer, Breast cancer families, Breast cancer family, Breast cancer risk, Breast cancer susceptibility, C3abr, Cancer, Cancer risk, Cell lines, Chromosomal, Chromosomal aberrations, Chromosome, Chromosomes cancer, Control cells, Control lcls, Damage repair, Differential expression, Differentially, Exon, Expression differences, Gene, Gene expression, Gene expression changes, Genes differentially, Genet, Genotype, Heterozygote, Heterozygote carriers, Heterozygote lcls, Heterozygous, Heterozygous carriers, Heterozygous lcls, Homozygote, Homozygous, Homozygous cells, Homozygous lcls, Index cases, Kconfab, Khanna, Kinase, Kinase activity, Kinase assays, Large number, Lcls, Mcm7, Metaphase spread, Microarray, Microarray experiments, Microarray results, Microarrays, Missense, Missense mutation, Multiple case breast cancer families, Mutation, Mutation carriers, Natl cancer inst, Nucleic acids, Null cells, Online issue, Penetrance, Phenotype, Phosphorylation, Pold1, Real time, Rfc5, Stankovic, Supplementary table, Telangiectasia, Truncating, Truncating mutation, Truncating mutations, Unrelated control pool, Unrelated controls, Unrelated pool, Validation, Vivo kinase assays.
- Teeft :
- Aberration, Array experiment, Assay, Ataxia, Ataxia telangiectasia, Breast, Breast cancer, Breast cancer families, Breast cancer family, Breast cancer risk, Breast cancer susceptibility, C3abr, Cancer, Cancer risk, Cell lines, Chromosomal, Chromosomal aberrations, Chromosome, Chromosomes cancer, Control cells, Control lcls, Damage repair, Differential expression, Differentially, Exon, Expression differences, Gene, Gene expression, Gene expression changes, Genes differentially, Genet, Genotype, Heterozygote, Heterozygote carriers, Heterozygote lcls, Heterozygous, Heterozygous carriers, Heterozygous lcls, Homozygote, Homozygous, Homozygous cells, Homozygous lcls, Index cases, Kconfab, Khanna, Kinase, Kinase activity, Kinase assays, Large number, Lcls, Mcm7, Metaphase spread, Microarray, Microarray experiments, Microarray results, Microarrays, Missense, Missense mutation, Multiple case breast cancer families, Mutation, Mutation carriers, Natl cancer inst, Nucleic acids, Null cells, Online issue, Penetrance, Phenotype, Phosphorylation, Pold1, Real time, Rfc5, Stankovic, Supplementary table, Telangiectasia, Truncating, Truncating mutation, Truncating mutations, Unrelated control pool, Unrelated controls, Unrelated pool, Validation, Vivo kinase assays.
Abstract
Mutations in ATM are responsible for the autosomal recessive disorder ataxia telangiectasia. Heterozygous mutations in ATM have been associated with an elevated risk of breast cancer. We previously reported one breast cancer family in which ATM 7271T>G (V2424G) segregated with disease, and apparently acted in a dominant negative manner. We now report the screening of 782 multiple‐case breast cancer families that identified two additional index cases with ATM 7271T>G. Phylogenetic sequence analysis showed that V2424 is a highly conserved residue, and that the 2424G variant is likely to interfere with function. To elucidate the consequences of this mutation, we expression profiled wild‐type, heterozygous, and homozygous lymphoblastoid cell lines (LCLs) from Scottish and Australian families using an oligonucleotide microarray. Cluster analysis revealed 77 genes that were differentially expressed in homozygous and heterozygous V2424G cells (compared to wild‐type) and 11 genes differentially expressed in the homozygous cells. We also evaluated the profiles of LCLs after exposure to ionizing radiation (IR) and identified 77 genes that were differentially expressed in wild‐type cells, but not in homozygous or heterozygous V2424G cells. We validated the expression differences by RT‐PCR in additional heterozygous V2424G LCLs from another breast cancer family. We found no consistent cytotoxicity or abrogation of ATM kinase activity after IR in seven heterozygous V2424G LCLs, compared to wild‐type LCLs, but did find an increase in the number of chromosomal aberrations. These data suggest that the V2424G missense mutation acts largely as a dominant negative in terms of the associated expression profiles. © 2006 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/gcc.20381
Affiliations:
- Allemagne, Australie, France, Royaume-Uni, États-Unis
- Angleterre, Australie-Méridionale, Auvergne-Rhône-Alpes, Midlands de l'Ouest, Rhône-Alpes, Utah, Victoria (État)
- Birmingham, Lyon, Melbourne
- Université de Birmingham, Université de Melbourne
Links toward previous steps (curation, corpus...)
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Le document en format XML
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Tavtigian</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>International Agency for Research into Cancer, Lyon</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName></affiliation></author><author><name sortKey="Suthers, Graeme" sort="Suthers, Graeme" uniqKey="Suthers G" first="Graeme" last="Suthers">Graeme Suthers</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatrics, University of Adelaide, South Australia</wicri:regionArea><wicri:noRegion>South Australia</wicri:noRegion></affiliation></author><author><name sortKey="Goldgar, David" sort="Goldgar, David" uniqKey="Goldgar D" first="David" last="Goldgar">David Goldgar</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Utah</region></placeName><wicri:cityArea>Department of Medical Informatics, University of Utah, Salt Lake City</wicri:cityArea></affiliation></author><author><name sortKey="Oefner, Peter J" sort="Oefner, Peter J" uniqKey="Oefner P" first="Peter J." last="Oefner">Peter J. Oefner</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Functional Genomics, University of Regensburg, Regensburg</wicri:regionArea><wicri:noRegion>Regensburg</wicri:noRegion><wicri:noRegion>Regensburg</wicri:noRegion></affiliation></author><author><name sortKey="Taylor, Darrin" sort="Taylor, Darrin" uniqKey="Taylor D" first="Darrin" last="Taylor">Darrin Taylor</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Biosciences, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Grimmond, Sean" sort="Grimmond, Sean" uniqKey="Grimmond S" first="Sean" last="Grimmond">Sean Grimmond</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Biosciences, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Khanna, Kum Kum" sort="Khanna, Kum Kum" uniqKey="Khanna K" first="Kum Kum" last="Khanna">Kum Kum Khanna</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Chenevix Rench, Georgia" sort="Chenevix Rench, Georgia" uniqKey="Chenevix Rench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Queensland Institute of Medical Research, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Australie</country></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Correspondence address: Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland, 4029</wicri:regionArea><wicri:noRegion>4029</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Genes, Chromosomes and Cancer</title><title level="j" type="alt">GENES, CHROMOSOMES AND CANCER</title><idno type="ISSN">1045-2257</idno><idno type="eISSN">1098-2264</idno><imprint><biblScope unit="vol">45</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="1169">1169</biblScope><biblScope unit="page" to="1181">1181</biblScope><biblScope unit="page-count">0</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2006-12">2006-12</date></imprint><idno type="ISSN">1045-2257</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1045-2257</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aberration</term><term>Array experiment</term><term>Assay</term><term>Ataxia</term><term>Ataxia telangiectasia</term><term>Breast</term><term>Breast cancer</term><term>Breast cancer families</term><term>Breast cancer family</term><term>Breast cancer risk</term><term>Breast cancer susceptibility</term><term>C3abr</term><term>Cancer</term><term>Cancer risk</term><term>Cell lines</term><term>Chromosomal</term><term>Chromosomal aberrations</term><term>Chromosome</term><term>Chromosomes cancer</term><term>Control cells</term><term>Control lcls</term><term>Damage repair</term><term>Differential expression</term><term>Differentially</term><term>Exon</term><term>Expression differences</term><term>Gene</term><term>Gene expression</term><term>Gene expression changes</term><term>Genes differentially</term><term>Genet</term><term>Genotype</term><term>Heterozygote</term><term>Heterozygote carriers</term><term>Heterozygote lcls</term><term>Heterozygous</term><term>Heterozygous carriers</term><term>Heterozygous lcls</term><term>Homozygote</term><term>Homozygous</term><term>Homozygous cells</term><term>Homozygous lcls</term><term>Index cases</term><term>Kconfab</term><term>Khanna</term><term>Kinase</term><term>Kinase activity</term><term>Kinase assays</term><term>Large number</term><term>Lcls</term><term>Mcm7</term><term>Metaphase spread</term><term>Microarray</term><term>Microarray experiments</term><term>Microarray results</term><term>Microarrays</term><term>Missense</term><term>Missense mutation</term><term>Multiple case breast cancer families</term><term>Mutation</term><term>Mutation carriers</term><term>Natl cancer inst</term><term>Nucleic acids</term><term>Null cells</term><term>Online issue</term><term>Penetrance</term><term>Phenotype</term><term>Phosphorylation</term><term>Pold1</term><term>Real time</term><term>Rfc5</term><term>Stankovic</term><term>Supplementary table</term><term>Telangiectasia</term><term>Truncating</term><term>Truncating mutation</term><term>Truncating mutations</term><term>Unrelated control pool</term><term>Unrelated controls</term><term>Unrelated pool</term><term>Validation</term><term>Vivo kinase assays</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Aberration</term><term>Array experiment</term><term>Assay</term><term>Ataxia</term><term>Ataxia telangiectasia</term><term>Breast</term><term>Breast cancer</term><term>Breast cancer families</term><term>Breast cancer family</term><term>Breast cancer risk</term><term>Breast cancer susceptibility</term><term>C3abr</term><term>Cancer</term><term>Cancer risk</term><term>Cell lines</term><term>Chromosomal</term><term>Chromosomal aberrations</term><term>Chromosome</term><term>Chromosomes cancer</term><term>Control cells</term><term>Control lcls</term><term>Damage repair</term><term>Differential expression</term><term>Differentially</term><term>Exon</term><term>Expression differences</term><term>Gene</term><term>Gene expression</term><term>Gene expression changes</term><term>Genes differentially</term><term>Genet</term><term>Genotype</term><term>Heterozygote</term><term>Heterozygote carriers</term><term>Heterozygote lcls</term><term>Heterozygous</term><term>Heterozygous carriers</term><term>Heterozygous lcls</term><term>Homozygote</term><term>Homozygous</term><term>Homozygous cells</term><term>Homozygous lcls</term><term>Index cases</term><term>Kconfab</term><term>Khanna</term><term>Kinase</term><term>Kinase activity</term><term>Kinase assays</term><term>Large number</term><term>Lcls</term><term>Mcm7</term><term>Metaphase spread</term><term>Microarray</term><term>Microarray experiments</term><term>Microarray results</term><term>Microarrays</term><term>Missense</term><term>Missense mutation</term><term>Multiple case breast cancer families</term><term>Mutation</term><term>Mutation carriers</term><term>Natl cancer inst</term><term>Nucleic acids</term><term>Null cells</term><term>Online issue</term><term>Penetrance</term><term>Phenotype</term><term>Phosphorylation</term><term>Pold1</term><term>Real time</term><term>Rfc5</term><term>Stankovic</term><term>Supplementary table</term><term>Telangiectasia</term><term>Truncating</term><term>Truncating mutation</term><term>Truncating mutations</term><term>Unrelated control pool</term><term>Unrelated controls</term><term>Unrelated pool</term><term>Validation</term><term>Vivo kinase assays</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Cancer</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in ATM are responsible for the autosomal recessive disorder ataxia telangiectasia. Heterozygous mutations in ATM have been associated with an elevated risk of breast cancer. We previously reported one breast cancer family in which ATM 7271T>G (V2424G) segregated with disease, and apparently acted in a dominant negative manner. We now report the screening of 782 multiple‐case breast cancer families that identified two additional index cases with ATM 7271T>G. Phylogenetic sequence analysis showed that V2424 is a highly conserved residue, and that the 2424G variant is likely to interfere with function. To elucidate the consequences of this mutation, we expression profiled wild‐type, heterozygous, and homozygous lymphoblastoid cell lines (LCLs) from Scottish and Australian families using an oligonucleotide microarray. Cluster analysis revealed 77 genes that were differentially expressed in homozygous and heterozygous V2424G cells (compared to wild‐type) and 11 genes differentially expressed in the homozygous cells. We also evaluated the profiles of LCLs after exposure to ionizing radiation (IR) and identified 77 genes that were differentially expressed in wild‐type cells, but not in homozygous or heterozygous V2424G cells. We validated the expression differences by RT‐PCR in additional heterozygous V2424G LCLs from another breast cancer family. We found no consistent cytotoxicity or abrogation of ATM kinase activity after IR in seven heterozygous V2424G LCLs, compared to wild‐type LCLs, but did find an increase in the number of chromosomal aberrations. These data suggest that the V2424G missense mutation acts largely as a dominant negative in terms of the associated expression profiles. © 2006 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Australie-Méridionale</li><li>Auvergne-Rhône-Alpes</li><li>Midlands de l'Ouest</li><li>Rhône-Alpes</li><li>Utah</li><li>Victoria (État)</li></region><settlement><li>Birmingham</li><li>Lyon</li><li>Melbourne</li></settlement><orgName><li>Université de Birmingham</li><li>Université de Melbourne</li></orgName></list><tree><country name="Australie"><noRegion><name sortKey="Waddell, Nic" sort="Waddell, Nic" uniqKey="Waddell N" first="Nic" last="Waddell">Nic Waddell</name></noRegion><name sortKey="Chenevix Rench, Georgia" sort="Chenevix Rench, Georgia" uniqKey="Chenevix Rench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><name sortKey="Chenevix Rench, Georgia" sort="Chenevix Rench, Georgia" uniqKey="Chenevix Rench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><name sortKey="Chenevix Rench, Georgia" sort="Chenevix Rench, Georgia" uniqKey="Chenevix Rench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><name sortKey="Grimmond, Sean" sort="Grimmond, Sean" uniqKey="Grimmond S" first="Sean" last="Grimmond">Sean Grimmond</name><name sortKey="Grist, Scott" sort="Grist, Scott" uniqKey="Grist S" first="Scott" last="Grist">Scott Grist</name><name sortKey="Hobson, Karen" sort="Hobson, Karen" uniqKey="Hobson K" first="Karen" last="Hobson">Karen Hobson</name><name sortKey="Jenkins, Mark" sort="Jenkins, Mark" uniqKey="Jenkins M" first="Mark" last="Jenkins">Mark Jenkins</name><name sortKey="Jonnalagadda, Jyoti" sort="Jonnalagadda, Jyoti" uniqKey="Jonnalagadda J" first="Jyoti" last="Jonnalagadda">Jyoti Jonnalagadda</name><name sortKey="Khanna, Kum Kum" sort="Khanna, Kum Kum" uniqKey="Khanna K" first="Kum Kum" last="Khanna">Kum Kum Khanna</name><name sortKey="Lindeman, Geoff J" sort="Lindeman, Geoff J" uniqKey="Lindeman G" first="Geoff J." last="Lindeman">Geoff J. Lindeman</name><name sortKey="Lindeman, Geoff J" sort="Lindeman, Geoff J" uniqKey="Lindeman G" first="Geoff J." last="Lindeman">Geoff J. Lindeman</name><name sortKey="Marsh, Anna" sort="Marsh, Anna" uniqKey="Marsh A" first="Anna" last="Marsh">Anna Marsh</name><name sortKey="Suthers, Graeme" sort="Suthers, Graeme" uniqKey="Suthers G" first="Graeme" last="Suthers">Graeme Suthers</name><name sortKey="Taylor, Darrin" sort="Taylor, Darrin" uniqKey="Taylor D" first="Darrin" last="Taylor">Darrin Taylor</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Taylor, Malcolm" sort="Taylor, Malcolm" uniqKey="Taylor M" first="Malcolm" last="Taylor">Malcolm Taylor</name></region></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name></region></country><country name="États-Unis"><region name="Utah"><name sortKey="Goldgar, David" sort="Goldgar, David" uniqKey="Goldgar D" first="David" last="Goldgar">David Goldgar</name></region></country><country name="Allemagne"><noRegion><name sortKey="Oefner, Peter J" sort="Oefner, Peter J" uniqKey="Oefner P" first="Peter J." last="Oefner">Peter J. Oefner</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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