Identification of Lynch syndrome among patients with colorectal cancer
CONTEXT: Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individual...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2012 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/68389 |
| Acesso em linha: | https://hdl.handle.net/2445/68389 |
| Access Level: | acceso abierto |
| Palavra-chave: | Càncer colorectal Genètica molecular Malalties hereditàries Anàlisi multivariable Colorectal cancer Molecular genetics Genetic diseases Multivariate analysis |
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Identification of Lynch syndrome among patients with colorectal cancerMoreira Ruiz, LeticiaBalaguer Prunés, FrancescLindor, NoralaneDe la Chapelle, AlbertHampel, HeatherAaltonen, Lauri A.Hopper, John L.Le Marchand, LoicGallinger, StevenNewcomb, Polly A.Haile, RobertThibodeau, Stephen NGunawardena, ShanakaJenkins, Mark A.Buchanan, Daniel D.Potter, John D.Baron, John A.Ahnen, Dennis J.Moreno Aguado, VíctorAndreu, MontserratPonz de Leon, MaurizioRustgi, Anil K.Castells Garangou, AntoniEPICOLON ConsortiumCàncer colorectalGenètica molecularMalalties hereditàriesAnàlisi multivariableColorectal cancerMolecular geneticsGenetic diseasesMultivariate analysisCONTEXT: Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. OBJECTIVE: To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. DESIGN, SETTING, AND PATIENTS: Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME: Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). RESULTS: Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. CONCLUSION: Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.American Medical Association2015201520122015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion11 p.application/pdfhttps://hdl.handle.net/2445/68389Articles publicats en revistes (Ciències Clíniques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: http://dx.doi.org/10.1001/jama.2012.13088JAMA-Journal of the American Medical Association, 2012, vol. 308, num. 15, p. 1555-1565http://dx.doi.org/10.1001/jama.2012.13088info:eu-repo/grantAgreement/EC/FP7/268648(c) American Medical Association, 2012info:eu-repo/semantics/openAccessoai:recercat.cat:2445/683892026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Identification of Lynch syndrome among patients with colorectal cancer |
| title |
Identification of Lynch syndrome among patients with colorectal cancer |
| spellingShingle |
Identification of Lynch syndrome among patients with colorectal cancer Moreira Ruiz, Leticia Càncer colorectal Genètica molecular Malalties hereditàries Anàlisi multivariable Colorectal cancer Molecular genetics Genetic diseases Multivariate analysis |
| title_short |
Identification of Lynch syndrome among patients with colorectal cancer |
| title_full |
Identification of Lynch syndrome among patients with colorectal cancer |
| title_fullStr |
Identification of Lynch syndrome among patients with colorectal cancer |
| title_full_unstemmed |
Identification of Lynch syndrome among patients with colorectal cancer |
| title_sort |
Identification of Lynch syndrome among patients with colorectal cancer |
| dc.creator.none.fl_str_mv |
Moreira Ruiz, Leticia Balaguer Prunés, Francesc Lindor, Noralane De la Chapelle, Albert Hampel, Heather Aaltonen, Lauri A. Hopper, John L. Le Marchand, Loic Gallinger, Steven Newcomb, Polly A. Haile, Robert Thibodeau, Stephen N Gunawardena, Shanaka Jenkins, Mark A. Buchanan, Daniel D. Potter, John D. Baron, John A. Ahnen, Dennis J. Moreno Aguado, Víctor Andreu, Montserrat Ponz de Leon, Maurizio Rustgi, Anil K. Castells Garangou, Antoni EPICOLON Consortium |
| author |
Moreira Ruiz, Leticia |
| author_facet |
Moreira Ruiz, Leticia Balaguer Prunés, Francesc Lindor, Noralane De la Chapelle, Albert Hampel, Heather Aaltonen, Lauri A. Hopper, John L. Le Marchand, Loic Gallinger, Steven Newcomb, Polly A. Haile, Robert Thibodeau, Stephen N Gunawardena, Shanaka Jenkins, Mark A. Buchanan, Daniel D. Potter, John D. Baron, John A. Ahnen, Dennis J. Moreno Aguado, Víctor Andreu, Montserrat Ponz de Leon, Maurizio Rustgi, Anil K. Castells Garangou, Antoni EPICOLON Consortium |
| author_role |
author |
| author2 |
Balaguer Prunés, Francesc Lindor, Noralane De la Chapelle, Albert Hampel, Heather Aaltonen, Lauri A. Hopper, John L. Le Marchand, Loic Gallinger, Steven Newcomb, Polly A. Haile, Robert Thibodeau, Stephen N Gunawardena, Shanaka Jenkins, Mark A. Buchanan, Daniel D. Potter, John D. Baron, John A. Ahnen, Dennis J. Moreno Aguado, Víctor Andreu, Montserrat Ponz de Leon, Maurizio Rustgi, Anil K. Castells Garangou, Antoni EPICOLON Consortium |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Càncer colorectal Genètica molecular Malalties hereditàries Anàlisi multivariable Colorectal cancer Molecular genetics Genetic diseases Multivariate analysis |
| topic |
Càncer colorectal Genètica molecular Malalties hereditàries Anàlisi multivariable Colorectal cancer Molecular genetics Genetic diseases Multivariate analysis |
| description |
CONTEXT: Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. OBJECTIVE: To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. DESIGN, SETTING, AND PATIENTS: Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME: Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). RESULTS: Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. CONCLUSION: Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest. |
| publishDate |
2012 |
| dc.date.none.fl_str_mv |
2012 2015 2015 2015 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/68389 |
| url |
https://hdl.handle.net/2445/68389 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: http://dx.doi.org/10.1001/jama.2012.13088 JAMA-Journal of the American Medical Association, 2012, vol. 308, num. 15, p. 1555-1565 http://dx.doi.org/10.1001/jama.2012.13088 info:eu-repo/grantAgreement/EC/FP7/268648 |
| dc.rights.none.fl_str_mv |
(c) American Medical Association, 2012 info:eu-repo/semantics/openAccess |
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(c) American Medical Association, 2012 |
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openAccess |
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11 p. application/pdf |
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American Medical Association |
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American Medical Association |
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Articles publicats en revistes (Ciències Clíniques) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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