No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2 : A Prospective Lynch Syndrome Database Study
Dominguez-Valentin, M., Plazzer, J.-P., Sampson, J. R., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Macrae, F., Winship, I. M., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Nielsen, M., . . . Møller, P. (2021). No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2 : A Prospective Lynch Syndrome Database Study. Journal of Clinical Medicine, 10(13), Article 2856. https://doi.org/10.3390/jcm10132856
Julkaistu sarjassa
Journal of Clinical MedicineTekijät
Päivämäärä
2021Tekijänoikeudet
© 2021 by the authors.
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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2077-0383Asiasanat
Julkaisu tutkimustietojärjestelmässä
https://converis.jyu.fi/converis/portal/detail/Publication/98997510
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We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017. The Colon CFR is supported in part by the National Cancer Institute of the National Institutes of Health under Award Number UM1CA167551. The Finnish contribution: Cancer Foundation Finland, Jane and Aatos Erkko Foundation, Emil Aaltonen Foundation, Finnish Medical Foundation, Sigrid Juselius Foundation, Instrumentarium Science Foundation, iCAN Flagship of the Academy of Finland. D.G.E. and E.J.C. are supported by the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007). The contribution from Wales was supported by the Wales Gene Park award from Health and Care Research Wales. The German Consortium for Familial Intestinal Cancer was supported by grants from the German Cancer Aid. Work by G.C., M.N., J.B., and M.P. was funded by the Spanish Ministry of Science and Innovation and cofounded by FEDER M.D. Catalonia (grants 2017SGR1282). The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.![showless](/themes/JYX2//images/showless.png)
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Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment : a report from the prospective Lynch syndrome database
Dominguez-Valentin, Mev; Haupt, Saskia; Seppälä, Toni T.; Sampson, Julian R.; Sunde, Lone; Bernstein, Inge; Jenkins, Mark A.; Engel, Christoph; Aretz, Stefan; Nielsen, Maartje; Capella, Gabriel; Balaguer, Francesc; Evans, Dafydd Gareth; Burn, John; Holinski-Feder, Elke; Bertario, Lucio; Bonanni, Bernardo; Lindblom, Annika; Levi, Zohar; Macrae, Finlay; Winship, Ingrid; Plazzer, John-Paul; Sijmons, Rolf; Laghi, Luigi; Della Valle, Adriana; Heinimann, Karl; Dębniak, Tadeusz; Fruscio, Robert; Lopez-Koestner, Francisco; Alvarez-Valenzuela, Karin; Katz, Lior H.; Laish, Ido; Vainer, Elez; Vaccaro, Carlos; Carraro, Dirce Maria; Monahan, Kevin; Half, Elizabeth; Stakelum, Aine; Winter, Des; Kennelly, Rory; Gluck, Nathan; Sheth, Harsh; Abu-Freha, Naim; Greenblatt, Marc; Rossi, Benedito Mauro; Bohorquez, Mabel; Cavestro, Giulia Martina; Lino-Silva, Leonardo S.; Horisberger, Karoline; Tibiletti, Maria Grazia; do Nascimento, Ivana; Thomas, Huw; Rossi, Norma Teresa; Apolinário da Silva, Leandro; Zaránd, Attila; Ruiz-Bañobre, Juan; Heuveline, Vincent; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Peltomäki, Päivi; Therkildsen, Christina; Madsen, Mia Gebauer; Burgdorf, Stefan Kobbelgaard; Hopper, John L.; Win, Aung Ko; Haile, Robert W.; Lindor, Noralane; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane; Buchanan, Daniel D.; Thibodeau, Stephen N.; von Knebel Doeberitz, Magnus; Loeffler, Markus; Rahner, Nils; Schröck, Evelin; Steinke-Lange, Verena; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Hüneburg, Robert; Redler, Silke; Büttner, Reinhard; Weitz, Jürgen; Pineda, Marta; Duenas, Nuria; Vidal, Joan Brunet; Moreira, Leticia; Sánchez, Ariadna; Hovig, Eivind; Nakken, Sigve; Green, Kate; Lalloo, Fiona; Hill, James; Crosbie, Emma; Mints, Miriam; Goldberg, Yael; Tjandra, Douglas; ten Broeke, Sanne W.; Kariv, Revital; Rosner, Guy; Advani, Suresh H.; Thomas, Lidiya; Shah, Pankaj; Shah, Mithun; Neffa, Florencia; Esperon, Patricia; Pavicic, Walter; Torrezan, Giovana Tardin; Bassaneze, Thiago; Martin, Claudia Alejandra; Moslein, Gabriela; Moller, Pål (Elsevier BV, 2023)Background The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, ... -
Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants : a Prospective Lynch Syndrome Database report
Dominguez-Valentin, Mev; Crosbie, Emma J.; Engel, Christoph; Aretz, Stefan; Macrae, Finlay; Winship, Ingrid; Capella, Gabriel; Thomas, Huw; Nakken, Sigve; Hovig, Eivind; Nielsen, Maartje; Sijmons, Rolf H.; Bertario, Lucio; Bonanni, Bernardo; Tibiletti, Maria Grazia; Cavestro, Giulia Martina; Mints, Miriam; Gluck, Nathan; Katz, Lior; Heinimann, Karl; Vaccaro, Carlos A.; Green, Kate; Lalloo, Fiona; Hill, James; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Strauß, Hans-Georg; Tecklenburg, Johanna; Holinski-Feder, Elke; Steinke-Lange, Verena; Mecklin, Jukka-Pekka; Plazzer, John-Paul; Pineda, Marta; Navarro, Matilde; Vidal, Joan Brunet; Kariv, Revital; Rosner, Guy; Piñero, Tamara Alejandra; Gonzalez, María Laura; Kalfayan, Pablo; Ryan, Neil; ten Broeke, Sanne W.; Jenkins, Mark A.; Sunde, Lone; Bernstein, Inge; Burn, John; Greenblatt, Marc; de Vos tot Nederveen Cappel, Wouter H.; Della, Valle Adriana; Lopez-Koestner, Francisco; Alvarez, Karin; Büttner, Reinhard; Görgens, Heike; Morak, Monika; Holzapfel, Stefanie; Hüneburg, Robert; von Knebel, Doeberitz Magnus; Loeffler, Markus; Rahner, Nils; Weitz, Jürgen; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Auranen, Annika; Hopper, John L.; Win, Aung Ko; Haile, Robert W.; Lindor, Noralane M.; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane C.; Thibodeau, Stephen N.; Therkildsen, Christina; Okkels, Henrik; Ketabi, Zohreh; Denton, Oliver G.; Rødland, Einar Andreas; Vasen, Hans; Neffa, Florencia; Esperon, Patricia; Tjandra, Douglas; Möslein, Gabriela; Sampson, Julian R.; Evans, D. Gareth; Seppälä, Toni T.; Møller, Pål (Nature Publishing Group, 2021)Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. Methods The ... -
Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report
Seppälä, Toni T.; Ahadova, Aysel; Dominguez-Valentin, Mev; Macrae, Finlay; Evans, D. Gareth; Therkildsen, Christina; Sampson, Julian; Scott, Rodney; Burn, John; Möslein, Gabriela; Bernstein, Inge; Holinski-Feder, Elke; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Lautrup, Charlotte Kvist; Lindblom, Annika; Plazzer, John-Paul; Winship, Ingrid; Tjandra, Douglas; Katz, Lior H.; Aretz, Stefan; Hüneburg, Robert; Holzapfel, Stefanie; Heinimann, Karl; Valle, Adriana Della; Neffa, Florencia; Gluck, Nathan; Cappel, Wouter H. de Vos tot Nederveen; Vasen, Hans; Morak, Monika; Steinke-Lange, Verena; Engel, Christoph; Rahner, Nils; Schmiegel, Wolff; Vangala, Deepak; Thomas, Huw; Green, Kate; Lalloo, Fiona; Crosbie, Emma J.; Hill, James; Capella, Gabriel; Pineda, Marta; Navarro, Matilde; Blanco, Ignacio; Broeke, Sanne ten; Nielsen, Maartje; Ljungmann, Ken; Nakken, Sigve; Lindor, Noralane; Frayling, Ian; Hovig, Eivind; Sunde, Lone; Kloor, Matthias; Mecklin, Jukka-Pekka; Kalager, Mette; Møller, Pål (BioMed Central Ltd., 2019)Background Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. ... -
Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants : findings from the Prospective Lynch Syndrome Database
Dominguez-Valentin, Mev; Sampson, Julian R.; Seppälä, Toni T.; ten Broeke, Sanne W.; Plazzer, John-Paul; Nakken, Sigve; Engel, Christoph; Aretz, Stefan; Jenkins, Mark A.; Sunde, Lone; Bernstein, Inge; Capella, Gabriel; Balaguer, Francesc; Thomas, Huw; Evans, D. Gareth; Burn, John; Greenblatt, Marc; Hovig, Eivind; de Vos tot Nederveen Cappel, Wouter H.; Sijmons, Rolf H.; Bertario, Lucio; Tibiletti, Maria Grazia; Cavestro, Giulia Martina; Lindblom, Annika; Della Valle, Adriana; Lopez-Köstner, Francisco; Gluck, Nathan; Katz, Lior H.; Heinimann, Karl; Vaccaro, Carlos A.; Büttner, Reinhard; Görgens, Heike; Holinski-Feder, Elke; Morak, Monika; Holzapfel, Stefanie; Hüneburg, Robert; Knebel Doeberitz, Magnus von; Loeffler, Markus; Rahner, Nils; Schackert, Hans K.; Steinke-Lange, Verena; Schmiegel, Wolff; Vangala, Deepak; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Hopper, John L.; Win, Aung Ko; Haile, Robert W.; Lindor, Noralane M.; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane C.; Thibodeau, Stephen N.; Wadt, Karin; Therkildsen, Christina; Okkels, Henrik; Ketabi, Zohreh; Moreira, Leticia; Sánchez, Ariadna; Serra-Burriel, Miquel; Pineda, Marta; Navarro, Matilde; Blanco, Ignacio; Green, Kate; Lalloo, Fiona; Crosbie, Emma J.; Hill, James; Denton, Oliver G.; Frayling, Ian M.; Rødland, Einar Andreas; Vasen, Hans; Mints, Miriam; Neffa, Florencia; Esperon, Patricia; Alvarez, Karin; Kariv, Revital; Rosner, Guy; Pinero, Tamara Alejandra; Gonzalez, María Laura; Kalfayan, Pablo; Tjandra, Douglas; Winship, Ingrid M.; Macrae, Finlay; Möslein, Gabriela; Mecklin, Jukka-Pekka; Nielsen, Maartje; Møller, Pål (Nature Publishing Group, 2020)PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according ... -
Colorectal cancer incidences in Lynch syndrome : a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
Møller, Pål; Seppälä, Toni; Dowty, James G.; Haupt, Saskia; Dominguez-Valentin, Mev; Sunde, Lone; Bernstein, Inge; Engel, Christoph; Aretz, Stefan; Nielsen, Maartje; Capella, Gabriel; Evans, Dafydd Gareth; Burn, John; Holinski-Feder, Elke; Bertario, Lucio; Bonanni, Bernardo; Lindblom, Annika; Levi, Zohar; Macrae, Finlay; Winship, Ingrid; Plazzer, John-Paul; Sijmons, Rolf; Laghi, Luigi; Valle Della, Adriana; Heinimann, Karl; Half, Elizabeth; Lopez-Koestner, Francisco; Alvarez-Valenzuela, Karin; Scott, Rodney J.; Katz, Lior; Laish, Ido; Vainer, Elez; Vaccaro, Carlos Alberto; Carraro, Dirce Maria; Gluck, Nathan; Abu-Freha, Naim; Stakelum, Aine; Kennelly, Rory; Winter, Des; Rossi, Benedito Mauro; Greenblatt, Marc; Bohorquez, Mabel; Sheth, Harsh; Tibiletti, Maria Grazia; Lino-Silva, Leonardo S.; Horisberger, Karoline; Portenkirchner, Carmen; Nascimento, Ivana; Rossi, Norma Teresa; da Silva, Leandro Apolinário; Thomas, Huw; Zaránd, Attila; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Peltomäki, Päivi; Therkildsen, Christina; Lindberg, Lars Joachim; Thorlacius-Ussing, Ole; von Knebel, Doeberitz Magnus; Loeffler, Markus; Rahner, Nils; Steinke-Lange, Verena; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Hüneburg, Robert; de Vargas, Aída Falcón; Latchford, Andrew; Gerdes, Anne-Marie; Backman, Ann-Sofie; Guillén-Ponce, Carmen; Snyder, Carrie; Lautrup, Charlotte K.; Amor, David; Palmero, Edenir; Stoffel, Elena; Duijkers, Floor; Hall, Michael J.; Hampel, Heather; Williams, Heinric; Okkels, Henrik; Lubiński, Jan; Reece, Jeanette; Ngeow, Joanne; Guillem, Jose G.; Arnold, Julie; Wadt, Karin; Monahan, Kevin; Senter, Leigha; Rasmussen, Lene J.; van Hest, Liselotte P.; Ricciardiello, Luigi; Kohonen-Corish, Maija R. J.; Ligtenberg, Marjolijn J. L.; Southey, Melissa; Aronson, Melyssa; Zahary, Mohd N.; Samadder, N. Jewel; Poplawski, Nicola; Hoogerbrugge, Nicoline; Morrison, Patrick J.; James, Paul; Lee, Grant; Chen-Shtoyerman, Rakefet; Ankathil, Ravindran; Pai, Rish; Ward, Robyn; Parry, Susan; Dębniak, Tadeusz; John, Thomas; van Overeem, Hansen Thomas; Caldés, Trinidad; Yamaguchi, Tatsuro; Barca-Tierno, Verónica; Garre, Pilar; Cavestro, Giulia Martina; Weitz, Jürgen; Redler, Silke; Büttner, Reinhard; Heuveline, Vincent; Hopper, John L.; Win, Aung Ko; Lindor, Noralane; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane; Buchanan, Daniel D.; Thibodeau, Stephen N.; ten Broeke, Sanne W.; Hovig, Eivind; Nakken, Sigve; Pineda, Marta; Dueñas, Nuria; Brunet, Joan; Green, Kate; Lalloo, Fiona; Newton, Katie; Crosbie, Emma J.; Mints, Miriam; Tjandra, Douglas; Neffa, Florencia; Esperon, Patricia; Kariv, Revital; Rosner, Guy; Pavicic, Walter Hernán; Kalfayan, Pablo; Torrezan, Giovana Tardin; Bassaneze, Thiago; Martin, Claudia; Moslein, Gabriela; Ahadova, Aysel; Kloor, Matthias; Sampson, Julian R.; Jenkins, Mark A.; The European Hereditary Tumour Group (EHTG); the International Mismatch Repair Consortium (IMRC) (Biomed Central, 2022)Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all ...
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