Clinical Classification of BRCA1 and BRCA2 DNA Sequence Variants : The Value of Cytokeratin Profiles and Evolutionary Analysis-A Report From the kConFab Investigators
Identifieur interne : 008E29 ( Main/Exploration ); précédent : 008E28; suivant : 008E30Clinical Classification of BRCA1 and BRCA2 DNA Sequence Variants : The Value of Cytokeratin Profiles and Evolutionary Analysis-A Report From the kConFab Investigators
Auteurs : Amanda B. Spurdle [Australie, France, États-Unis] ; Sunil R. Lakhani ; Sue Healey ; Suzanne Parry ; Leonard M. Da Silva ; Ross Brinkworth ; John L. Hopper ; Melissa A. Brown ; Davit Babikyan ; Georgia Chenevix-Trench ; Sean V. Tavtigian ; David E. GoldgarSource :
- Journal of clinical oncology [ 0732-183X ] ; 2008.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Classification.
English descriptors
- KwdEn :
Abstract
Purpose Rare missense substitutions and in-frame deletions of BRCA1 and BRCA2 genes present a challenge for genetic counseling of individuals carrying such unclassified variants. We assessed the value of tumor immunohistochemical markers in conjunction with genetic and evolutionary approaches for investigating the clinical significance of unclassified variants. Patients and Methods We studied 10 BRCA1 and 12 BRCA2 variants identified in Australian families with breast cancer. Analyses assumed a prior probability based on revised cross-species sequence alignment methods assessing amino acid evolutionary conservation and position, combined with likelihoods from data on co-occurrence with pathogenic mutations in the same gene, segregation analysis, and immunohistochemistry. We specifically explored the value of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 as tumor markers of BRCA1 mutation status. Results Posterior probabilities classified 72% of variants. BRCA variants IVS18+1 G>T (del exon 18) and 5632 T >A (V1838E) were classified as pathogenic, with >99% posterior probability of being deleterious, and tumor histopathology was particularly important for their classification. BRCA2 variant classification was improved over previous studies, largely by incorporating the prior probability of pathogenicity based on amino acid cross-species sequence alignments. Conclusion Variant classification was considerably improved by analysis of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumor expression, and use of updated methods estimating the clinical relevance of amino acid evolutionary conservation and position. These methodologies may assist genetic counseling of individuals with unclassified sequence variants.
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Spurdle</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Queensland Institute of Medical Research</s1><s3>AUS</s3></inist:fA14><country>Australie</country><wicri:noRegion>Queensland Institute of Medical Research</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>School of Medicine, and School of Molecular and Microbial Sciences, University of Queensland</s1><s2>Brisbane</s2><s3>AUS</s3></inist:fA14><country>Australie</country><wicri:noRegion>Brisbane</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Centre for Genetic Epidemiology, University of Melbourne and Peter MacCallum Cancer Centre</s1><s2>Melbourne</s2><s3>AUS</s3></inist:fA14><country>Australie</country><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>International Agency for Research on Cancer</s1><s2>Lyon</s2><s3>FRA</s3></inist:fA14><country>France</country><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Dermatology, University of Utah</s1><s2>Salt Lake City, UT</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><wicri:noRegion>Salt Lake City, UT</wicri:noRegion></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R." last="Lakhani">Sunil R. Lakhani</name></author><author><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name></author><author><name sortKey="Parry, Suzanne" sort="Parry, Suzanne" uniqKey="Parry S" first="Suzanne" last="Parry">Suzanne Parry</name></author><author><name sortKey="Da Silva, Leonard M" sort="Da Silva, Leonard M" uniqKey="Da Silva L" first="Leonard M." last="Da Silva">Leonard M. Da Silva</name></author><author><name sortKey="Brinkworth, Ross" sort="Brinkworth, Ross" uniqKey="Brinkworth R" first="Ross" last="Brinkworth">Ross Brinkworth</name></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name></author><author><name sortKey="Brown, Melissa A" sort="Brown, Melissa A" uniqKey="Brown M" first="Melissa A." last="Brown">Melissa A. Brown</name></author><author><name sortKey="Babikyan, Davit" sort="Babikyan, Davit" uniqKey="Babikyan D" first="Davit" last="Babikyan">Davit Babikyan</name></author><author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name></author><author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name></author><author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name></author></analytic><series><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>BRCA1 gene</term><term>BRCA2 gene</term><term>Biological evolution</term><term>Cancerology</term><term>Classification</term><term>Cytokeratin</term><term>Genetic variability</term><term>Nucleotide sequence</term><term>Tumor suppressor gene</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Classification</term><term>Gène BRCA1</term><term>Gène suppresseur tumeur</term><term>Gène BRCA2</term><term>Séquence nucléotide</term><term>Variabilité génétique</term><term>Cytokératine</term><term>Evolution biologique</term><term>Cancérologie</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Classification</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose Rare missense substitutions and in-frame deletions of BRCA1 and BRCA2 genes present a challenge for genetic counseling of individuals carrying such unclassified variants. We assessed the value of tumor immunohistochemical markers in conjunction with genetic and evolutionary approaches for investigating the clinical significance of unclassified variants. Patients and Methods We studied 10 BRCA1 and 12 BRCA2 variants identified in Australian families with breast cancer. Analyses assumed a prior probability based on revised cross-species sequence alignment methods assessing amino acid evolutionary conservation and position, combined with likelihoods from data on co-occurrence with pathogenic mutations in the same gene, segregation analysis, and immunohistochemistry. We specifically explored the value of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 as tumor markers of BRCA1 mutation status. Results Posterior probabilities classified 72% of variants. BRCA variants IVS18+1 G>T (del exon 18) and 5632 T >A (V1838E) were classified as pathogenic, with >99% posterior probability of being deleterious, and tumor histopathology was particularly important for their classification. BRCA2 variant classification was improved over previous studies, largely by incorporating the prior probability of pathogenicity based on amino acid cross-species sequence alignments. Conclusion Variant classification was considerably improved by analysis of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumor expression, and use of updated methods estimating the clinical relevance of amino acid evolutionary conservation and position. These methodologies may assist genetic counseling of individuals with unclassified sequence variants.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>États-Unis</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Rhône-Alpes</li><li>Victoria (État)</li></region><settlement><li>Lyon</li><li>Melbourne</li></settlement></list><tree><noCountry><name sortKey="Babikyan, Davit" sort="Babikyan, Davit" uniqKey="Babikyan D" first="Davit" last="Babikyan">Davit Babikyan</name><name sortKey="Brinkworth, Ross" sort="Brinkworth, Ross" uniqKey="Brinkworth R" first="Ross" last="Brinkworth">Ross Brinkworth</name><name sortKey="Brown, Melissa A" sort="Brown, Melissa A" uniqKey="Brown M" first="Melissa A." last="Brown">Melissa A. Brown</name><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><name sortKey="Da Silva, Leonard M" sort="Da Silva, Leonard M" uniqKey="Da Silva L" first="Leonard M." last="Da Silva">Leonard M. Da Silva</name><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R." last="Lakhani">Sunil R. Lakhani</name><name sortKey="Parry, Suzanne" sort="Parry, Suzanne" uniqKey="Parry S" first="Suzanne" last="Parry">Suzanne Parry</name><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name></noCountry><country name="Australie"><noRegion><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name></noRegion><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. 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