Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study
Identifieur interne : 006053 ( Main/Exploration ); précédent : 006052; suivant : 006054Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study
Auteurs : Florence Le Calvez-Kelm [France] ; Fabienne Lesueur [France] ; Francesca Damiola [France] ; Maxime Vallée [France] ; Catherine Voegele [France] ; Davit Babikyan [Arménie] ; Geoffroy Durand [France] ; Nathalie Forey [France] ; Sandrine Mckay-Chopin [France] ; Nivonirina Robinot [France] ; Tù Nguyen-Dumont [France] ; Alun Thomas [États-Unis] ; Graham B. Byrnes [France] ; John L. Hopper [Australie] ; Melissa C. Southey [Australie] ; Irene L. Andrulis [Canada] ; Esther M. John [États-Unis] ; Sean V. Tavtigian [États-Unis]Source :
- Breast Cancer Research : BCR [ 1465-5411 ] ; 2011.
Abstract
Both protein-truncating variants and some missense substitutions in
Previously, we adapted an
We found evidence of risk associated with rare, evolutionarily unlikely
This study shows that
Url:
DOI: 10.1186/bcr2810
PubMed: 21244692
PubMed Central: 3109572
Affiliations:
- Arménie, Australie, Canada, France, États-Unis
- Auvergne-Rhône-Alpes, Californie, Ontario, Rhône-Alpes, Utah, Victoria (État)
- Melbourne, Toronto
- Université de Melbourne, Université de Toronto
Links toward previous steps (curation, corpus...)
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- to stream Pmc, to step Curation: 002210
- to stream Pmc, to step Checkpoint: 002189
- to stream Ncbi, to step Merge: 000960
- to stream Ncbi, to step Curation: 000960
- to stream Ncbi, to step Checkpoint: 000960
- to stream Main, to step Merge: 006390
- to stream Main, to step Curation: 006053
Le document en format XML
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contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study</title>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Rare, evolutionarily unlikely missense substitutions in <italic>CHEK2 </italic>
contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study</title>
<author><name sortKey="Le Calvez Kelm, Florence" sort="Le Calvez Kelm, Florence" uniqKey="Le Calvez Kelm F" first="Florence" last="Le Calvez-Kelm">Florence Le Calvez-Kelm</name>
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</affiliation>
</author>
<author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L" last="Hopper">John L. Hopper</name>
<affiliation wicri:level="4"><nlm:aff id="I4">Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, 723 Swanston Street, Melbourne, Victoria 3010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, 723 Swanston Street, Melbourne, Victoria 3010</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name>
<affiliation wicri:level="4"><nlm:aff id="I7">Department of Pathology, The University of Melbourne, Medical Building 181, Melbourne, Victoria 3010, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Pathology, The University of Melbourne, Medical Building 181, Melbourne, Victoria 3010</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L" last="Andrulis">Irene L. Andrulis</name>
<affiliation wicri:level="4"><nlm:aff id="I5">Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, 60 Murray Street, Toronto, ON M5T 3L9, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, 60 Murray Street, Toronto, ON M5T 3L9</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M" last="John">Esther M. John</name>
<affiliation wicri:level="2"><nlm:aff id="I6">Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="I8">Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V" last="Tavtigian">Sean V. Tavtigian</name>
<affiliation wicri:level="2"><nlm:aff id="I9">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, 2000 Circle of Hope, Salt Lake City, UT 84112, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, 2000 Circle of Hope, Salt Lake City, UT 84112</wicri:regionArea>
<placeName><region type="state">Utah</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Breast Cancer Research : BCR</title>
<idno type="ISSN">1465-5411</idno>
<idno type="eISSN">1465-542X</idno>
<imprint><date when="2011">2011</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Introduction</title>
<p>Both protein-truncating variants and some missense substitutions in <italic>CHEK2 </italic>
confer increased risk of breast cancer. However, no large-scale study has used full open reading frame mutation screening to assess the contribution of rare missense substitutions in <italic>CHEK2 </italic>
to breast cancer risk. This absence has been due in part to a lack of validated statistical methods for summarizing risk attributable to large numbers of individually rare missense substitutions.</p>
</sec>
<sec><title>Methods</title>
<p>Previously, we adapted an <italic>in silico </italic>
assessment of missense substitutions used for analysis of unclassified missense substitutions in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
to the problem of assessing candidate genes using rare missense substitution data observed in case-control mutation-screening studies. The method involves stratifying rare missense substitutions observed in cases and/or controls into a series of grades ordered <italic>a priori </italic>
from least to most likely to be evolutionarily deleterious, followed by a logistic regression test for trends to compare the frequency distributions of the graded missense substitutions in cases versus controls. Here we used this approach to analyze <italic>CHEK2 </italic>
mutation-screening data from a population-based series of 1,303 female breast cancer patients and 1,109 unaffected female controls.</p>
</sec>
<sec><title>Results</title>
<p>We found evidence of risk associated with rare, evolutionarily unlikely <italic>CHEK2 </italic>
missense substitutions. Additional findings were that (1) the risk estimate for the most severe grade of <italic>CHEK2 </italic>
missense substitutions (denoted C65) is approximately equivalent to that of <italic>CHEK2 </italic>
protein-truncating variants; (2) the population attributable fraction and the familial relative risk explained by the pool of rare missense substitutions were similar to those explained by the pool of protein-truncating variants; and (3) <italic>post hoc </italic>
power calculations implied that scaling up case-control mutation screening to examine entire biochemical pathways would require roughly 2,000 cases and controls to achieve acceptable statistical power.</p>
</sec>
<sec><title>Conclusions</title>
<p>This study shows that <italic>CHEK2 </italic>
harbors many rare sequence variants that confer increased risk of breast cancer and that a substantial proportion of these are missense substitutions. The study validates our analytic approach to rare missense substitutions and provides a method to combine data from protein-truncating variants and rare missense substitutions into a one degree of freedom per gene test.</p>
</sec>
</div>
</front>
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<author><name sortKey="Eccles, Dm" uniqKey="Eccles D">DM Eccles</name>
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<author><name sortKey="Easton, D" uniqKey="Easton D">D Easton</name>
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<author><name sortKey="Foulkes, Wd" uniqKey="Foulkes W">WD Foulkes</name>
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<author><name sortKey="Genuardi, M" uniqKey="Genuardi M">M Genuardi</name>
</author>
<author><name sortKey="Greenblatt, Ms" uniqKey="Greenblatt M">MS Greenblatt</name>
</author>
<author><name sortKey="Hogervorst, Fb" uniqKey="Hogervorst F">FB Hogervorst</name>
</author>
<author><name sortKey="Hoogerbrugge, N" uniqKey="Hoogerbrugge N">N Hoogerbrugge</name>
</author>
<author><name sortKey="Spurdle, Ab" uniqKey="Spurdle A">AB Spurdle</name>
</author>
<author><name sortKey="Tavtigian, Sv" uniqKey="Tavtigian S">SV Tavtigian</name>
</author>
</analytic>
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<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Johnson, N" uniqKey="Johnson N">N Johnson</name>
</author>
<author><name sortKey="Fletcher, O" uniqKey="Fletcher O">O Fletcher</name>
</author>
<author><name sortKey="Naceur Lombardelli, C" uniqKey="Naceur Lombardelli C">C Naceur-Lombardelli</name>
</author>
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</author>
<author><name sortKey="Peto, J" uniqKey="Peto J">J Peto</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Byrnes, Gb" uniqKey="Byrnes G">GB Byrnes</name>
</author>
<author><name sortKey="Southey, Mc" uniqKey="Southey M">MC Southey</name>
</author>
<author><name sortKey="Hopper, Jl" uniqKey="Hopper J">JL Hopper</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Narod, Sa" uniqKey="Narod S">SA Narod</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bernstein, Jl" uniqKey="Bernstein J">JL Bernstein</name>
</author>
<author><name sortKey="Haile, Rw" uniqKey="Haile R">RW Haile</name>
</author>
<author><name sortKey="Stovall, M" uniqKey="Stovall M">M Stovall</name>
</author>
<author><name sortKey="Boice, Jdj" uniqKey="Boice J">JDJ Boice</name>
</author>
<author><name sortKey="Shore, Re" uniqKey="Shore R">RE Shore</name>
</author>
<author><name sortKey="Langholz, B" uniqKey="Langholz B">B Langholz</name>
</author>
<author><name sortKey="Thomas, Dc" uniqKey="Thomas D">DC Thomas</name>
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<author><name sortKey="Bernstein, L" uniqKey="Bernstein L">L Bernstein</name>
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<author><name sortKey="Lynch, Cf" uniqKey="Lynch C">CF Lynch</name>
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<author><name sortKey="Olsen, Jh" uniqKey="Olsen J">JH Olsen</name>
</author>
<author><name sortKey="Malone, Ke" uniqKey="Malone K">KE Malone</name>
</author>
<author><name sortKey="Mellemkjaer, L" uniqKey="Mellemkjaer L">L Mellemkjaer</name>
</author>
<author><name sortKey="Borresen Dale, Al" uniqKey="Borresen Dale A">AL Borresen-Dale</name>
</author>
<author><name sortKey="Rosenstein, Bs" uniqKey="Rosenstein B">BS Rosenstein</name>
</author>
<author><name sortKey="Teraoka, Sn" uniqKey="Teraoka S">SN Teraoka</name>
</author>
<author><name sortKey="Diep, At" uniqKey="Diep A">AT Diep</name>
</author>
<author><name sortKey="Smith, Sa" uniqKey="Smith S">SA Smith</name>
</author>
<author><name sortKey="Capanu, M" uniqKey="Capanu M">M Capanu</name>
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</author>
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</author>
<author><name sortKey="Gatti, Ra" uniqKey="Gatti R">RA Gatti</name>
</author>
<author><name sortKey="Concannon, P" uniqKey="Concannon P">P Concannon</name>
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<author><name sortKey="Lee, Mk" uniqKey="Lee M">MK Lee</name>
</author>
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<author><name sortKey="Thornton, Am" uniqKey="Thornton A">AM Thornton</name>
</author>
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</author>
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</author>
<author><name sortKey="Nord, As" uniqKey="Nord A">AS Nord</name>
</author>
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</author>
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</author>
<author><name sortKey="King, Mc" uniqKey="King M">MC King</name>
</author>
</analytic>
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</author>
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</author>
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<author><name sortKey="Parry, S" uniqKey="Parry S">S Parry</name>
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<author><name sortKey="Da Silva, Lm" uniqKey="Da Silva L">LM Da Silva</name>
</author>
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<author><name sortKey="Chenevix Trench, G" uniqKey="Chenevix Trench G">G Chenevix-Trench</name>
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<author><name sortKey="Goldgar, De" uniqKey="Goldgar D">DE Goldgar</name>
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<li>Australie</li>
<li>Canada</li>
<li>France</li>
<li>États-Unis</li>
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<region><li>Auvergne-Rhône-Alpes</li>
<li>Californie</li>
<li>Ontario</li>
<li>Rhône-Alpes</li>
<li>Utah</li>
<li>Victoria (État)</li>
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<settlement><li>Melbourne</li>
<li>Toronto</li>
</settlement>
<orgName><li>Université de Melbourne</li>
<li>Université de Toronto</li>
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</list>
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<name sortKey="Lesueur, Fabienne" sort="Lesueur, Fabienne" uniqKey="Lesueur F" first="Fabienne" last="Lesueur">Fabienne Lesueur</name>
<name sortKey="Mckay Chopin, Sandrine" sort="Mckay Chopin, Sandrine" uniqKey="Mckay Chopin S" first="Sandrine" last="Mckay-Chopin">Sandrine Mckay-Chopin</name>
<name sortKey="Nguyen Dumont, Tu" sort="Nguyen Dumont, Tu" uniqKey="Nguyen Dumont T" first="Tù" last="Nguyen-Dumont">Tù Nguyen-Dumont</name>
<name sortKey="Robinot, Nivonirina" sort="Robinot, Nivonirina" uniqKey="Robinot N" first="Nivonirina" last="Robinot">Nivonirina Robinot</name>
<name sortKey="Vallee, Maxime" sort="Vallee, Maxime" uniqKey="Vallee M" first="Maxime" last="Vallée">Maxime Vallée</name>
<name sortKey="Voegele, Catherine" sort="Voegele, Catherine" uniqKey="Voegele C" first="Catherine" last="Voegele">Catherine Voegele</name>
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<country name="Arménie"><noRegion><name sortKey="Babikyan, Davit" sort="Babikyan, Davit" uniqKey="Babikyan D" first="Davit" last="Babikyan">Davit Babikyan</name>
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<name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M" last="John">Esther M. John</name>
<name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M" last="John">Esther M. John</name>
<name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V" last="Tavtigian">Sean V. Tavtigian</name>
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<country name="Australie"><region name="Victoria (État)"><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L" last="Hopper">John L. Hopper</name>
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<name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name>
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<country name="Canada"><region name="Ontario"><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L" last="Andrulis">Irene L. Andrulis</name>
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</record>
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