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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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AT moreiraleticia nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT sanchezariadna nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT serraburrielmiquel nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT mintsmiriam nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT karivrevital nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT rosnerguy nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT pinerotamaraalejandra nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT pavicicwalterhernan nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT kalfayanpablo nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT broekesannewten nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT mecklinjukkapekka nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT pylvanainenkirsi nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT renkonensinisalolaura nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT lepistoanna nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT peltomakipaivi nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT hopperjohnl nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT winaungko nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT buchanandanield nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT lindornoralanem nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT gallingersteven nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT marchandloicle nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT newcombpollya nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT figueiredojanec nodifferenceinpenetrancebetweentruncatingandmissenseaberrantsplicingpathogenicvariantsinmlh1andmsh2aprospectivelynchsyndromedatabasestudy
AT thibodeaustephenn 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