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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene i...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121/ https://www.ncbi.nlm.nih.gov/pubmed/34203177 http://dx.doi.org/10.3390/jcm10132856 |
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author | Dominguez-Valentin, Mev Plazzer, John-Paul Sampson, Julian R. Engel, Christoph Aretz, Stefan Jenkins, Mark A. Sunde, Lone Bernstein, Inge Capella, Gabriel Balaguer, Francesc Macrae, Finlay Winship, Ingrid M. Thomas, Huw Evans, Dafydd Gareth Burn, John Greenblatt, Marc de Vos tot Nederveen Cappel, Wouter H. Sijmons, Rolf H. Nielsen, Maartje Bertario, Lucio Bonanni, Bernardo Tibiletti, Maria Grazia Cavestro, Giulia Martina Lindblom, Annika Valle, Adriana Della Lopez-Kostner, Francisco Alvarez, Karin Gluck, Nathan Katz, Lior Heinimann, Karl Vaccaro, Carlos A. Nakken, Sigve Hovig, Eivind Green, Kate Lalloo, Fiona Hill, James Vasen, Hans F. A. Perne, Claudia Büttner, Reinhard Görgens, Heike Holinski-Feder, Elke Morak, Monika Holzapfel, Stefanie Hüneburg, Robert von Knebel Doeberitz, Magnus Loeffler, Markus Rahner, Nils Weitz, Jürgen Steinke-Lange, Verena Schmiegel, Wolff Vangala, Deepak Crosbie, Emma J. Pineda, Marta Navarro, Matilde Brunet, Joan Moreira, Leticia Sánchez, Ariadna Serra-Burriel, Miquel Mints, Miriam Kariv, Revital Rosner, Guy Piñero, Tamara Alejandra Pavicic, Walter Hernán Kalfayan, Pablo Broeke, Sanne W. ten Mecklin, Jukka-Pekka Pylvänäinen, Kirsi Renkonen-Sinisalo, Laura Lepistö, Anna Peltomäki, Päivi Hopper, John L. Win, Aung Ko Buchanan, Daniel D. Lindor, Noralane M. Gallinger, Steven Marchand, Loïc Le Newcomb, Polly A. Figueiredo, Jane C. Thibodeau, Stephen N. Therkildsen, Christina Hansen, Thomas V. O. Lindberg, Lars Rødland, Einar Andreas Neffa, Florencia Esperon, Patricia Tjandra, Douglas Möslein, Gabriela Seppälä, Toni T. Møller, Pål |
author_facet | Dominguez-Valentin, Mev Plazzer, John-Paul Sampson, Julian R. Engel, Christoph Aretz, Stefan Jenkins, Mark A. Sunde, Lone Bernstein, Inge Capella, Gabriel Balaguer, Francesc Macrae, Finlay Winship, Ingrid M. Thomas, Huw Evans, Dafydd Gareth Burn, John Greenblatt, Marc de Vos tot Nederveen Cappel, Wouter H. Sijmons, Rolf H. Nielsen, Maartje Bertario, Lucio Bonanni, Bernardo Tibiletti, Maria Grazia Cavestro, Giulia Martina Lindblom, Annika Valle, Adriana Della Lopez-Kostner, Francisco Alvarez, Karin Gluck, Nathan Katz, Lior Heinimann, Karl Vaccaro, Carlos A. Nakken, Sigve Hovig, Eivind Green, Kate Lalloo, Fiona Hill, James Vasen, Hans F. A. Perne, Claudia Büttner, Reinhard Görgens, Heike Holinski-Feder, Elke Morak, Monika Holzapfel, Stefanie Hüneburg, Robert von Knebel Doeberitz, Magnus Loeffler, Markus Rahner, Nils Weitz, Jürgen Steinke-Lange, Verena Schmiegel, Wolff Vangala, Deepak Crosbie, Emma J. Pineda, Marta Navarro, Matilde Brunet, Joan Moreira, Leticia Sánchez, Ariadna Serra-Burriel, Miquel Mints, Miriam Kariv, Revital Rosner, Guy Piñero, Tamara Alejandra Pavicic, Walter Hernán Kalfayan, Pablo Broeke, Sanne W. ten Mecklin, Jukka-Pekka Pylvänäinen, Kirsi Renkonen-Sinisalo, Laura Lepistö, Anna Peltomäki, Päivi Hopper, John L. Win, Aung Ko Buchanan, Daniel D. Lindor, Noralane M. Gallinger, Steven Marchand, Loïc Le Newcomb, Polly A. Figueiredo, Jane C. Thibodeau, Stephen N. Therkildsen, Christina Hansen, Thomas V. O. Lindberg, Lars Rødland, Einar Andreas Neffa, Florencia Esperon, Patricia Tjandra, Douglas Möslein, Gabriela Seppälä, Toni T. Møller, Pål |
author_sort | Dominguez-Valentin, Mev |
collection | PubMed |
description | Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2. |
format | Online Article Text |
id | pubmed-8269121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82691212021-07-10 No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study Dominguez-Valentin, Mev Plazzer, John-Paul Sampson, Julian R. Engel, Christoph Aretz, Stefan Jenkins, Mark A. Sunde, Lone Bernstein, Inge Capella, Gabriel Balaguer, Francesc Macrae, Finlay Winship, Ingrid M. Thomas, Huw Evans, Dafydd Gareth Burn, John Greenblatt, Marc de Vos tot Nederveen Cappel, Wouter H. Sijmons, Rolf H. Nielsen, Maartje Bertario, Lucio Bonanni, Bernardo Tibiletti, Maria Grazia Cavestro, Giulia Martina Lindblom, Annika Valle, Adriana Della Lopez-Kostner, Francisco Alvarez, Karin Gluck, Nathan Katz, Lior Heinimann, Karl Vaccaro, Carlos A. Nakken, Sigve Hovig, Eivind Green, Kate Lalloo, Fiona Hill, James Vasen, Hans F. A. Perne, Claudia Büttner, Reinhard Görgens, Heike Holinski-Feder, Elke Morak, Monika Holzapfel, Stefanie Hüneburg, Robert von Knebel Doeberitz, Magnus Loeffler, Markus Rahner, Nils Weitz, Jürgen Steinke-Lange, Verena Schmiegel, Wolff Vangala, Deepak Crosbie, Emma J. Pineda, Marta Navarro, Matilde Brunet, Joan Moreira, Leticia Sánchez, Ariadna Serra-Burriel, Miquel Mints, Miriam Kariv, Revital Rosner, Guy Piñero, Tamara Alejandra Pavicic, Walter Hernán Kalfayan, Pablo Broeke, Sanne W. ten Mecklin, Jukka-Pekka Pylvänäinen, Kirsi Renkonen-Sinisalo, Laura Lepistö, Anna Peltomäki, Päivi Hopper, John L. Win, Aung Ko Buchanan, Daniel D. Lindor, Noralane M. Gallinger, Steven Marchand, Loïc Le Newcomb, Polly A. Figueiredo, Jane C. Thibodeau, Stephen N. Therkildsen, Christina Hansen, Thomas V. O. Lindberg, Lars Rødland, Einar Andreas Neffa, Florencia Esperon, Patricia Tjandra, Douglas Möslein, Gabriela Seppälä, Toni T. Møller, Pål J Clin Med Article Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2. MDPI 2021-06-28 /pmc/articles/PMC8269121/ /pubmed/34203177 http://dx.doi.org/10.3390/jcm10132856 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dominguez-Valentin, Mev Plazzer, John-Paul Sampson, Julian R. Engel, Christoph Aretz, Stefan Jenkins, Mark A. Sunde, Lone Bernstein, Inge Capella, Gabriel Balaguer, Francesc Macrae, Finlay Winship, Ingrid M. Thomas, Huw Evans, Dafydd Gareth Burn, John Greenblatt, Marc de Vos tot Nederveen Cappel, Wouter H. Sijmons, Rolf H. Nielsen, Maartje Bertario, Lucio Bonanni, Bernardo Tibiletti, Maria Grazia Cavestro, Giulia Martina Lindblom, Annika Valle, Adriana Della Lopez-Kostner, Francisco Alvarez, Karin Gluck, Nathan Katz, Lior Heinimann, Karl Vaccaro, Carlos A. Nakken, Sigve Hovig, Eivind Green, Kate Lalloo, Fiona Hill, James Vasen, Hans F. A. Perne, Claudia Büttner, Reinhard Görgens, Heike Holinski-Feder, Elke Morak, Monika Holzapfel, Stefanie Hüneburg, Robert von Knebel Doeberitz, Magnus Loeffler, Markus Rahner, Nils Weitz, Jürgen Steinke-Lange, Verena Schmiegel, Wolff Vangala, Deepak Crosbie, Emma J. Pineda, Marta Navarro, Matilde Brunet, Joan Moreira, Leticia Sánchez, Ariadna Serra-Burriel, Miquel Mints, Miriam Kariv, Revital Rosner, Guy Piñero, Tamara Alejandra Pavicic, Walter Hernán Kalfayan, Pablo Broeke, Sanne W. ten Mecklin, Jukka-Pekka Pylvänäinen, Kirsi Renkonen-Sinisalo, Laura Lepistö, Anna Peltomäki, Päivi Hopper, John L. Win, Aung Ko Buchanan, Daniel D. Lindor, Noralane M. Gallinger, Steven Marchand, Loïc Le Newcomb, Polly A. Figueiredo, Jane C. Thibodeau, Stephen N. Therkildsen, Christina Hansen, Thomas V. O. Lindberg, Lars Rødland, Einar Andreas Neffa, Florencia Esperon, Patricia Tjandra, Douglas Möslein, Gabriela Seppälä, Toni T. Møller, Pål No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study |
title | No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study |
title_full | No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study |
title_fullStr | No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study |
title_full_unstemmed | No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study |
title_short | No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study |
title_sort | no difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2: a prospective lynch syndrome database study |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121/ https://www.ncbi.nlm.nih.gov/pubmed/34203177 http://dx.doi.org/10.3390/jcm10132856 |
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nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT therkildsenchristina nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT hansenthomasvo nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT lindberglars nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT rødlandeinarandreas nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT neffaflorencia nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT esperonpatricia nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT tjandradouglas nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT mosleingabriela nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT seppalatonit nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy AT møllerpal nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy |