Dominguez-Valentin, Mev ORCID: 0000-0001-7856-0057, Plazzer, John-Paul ORCID: 0000-0001-5114-4301, Sampson, Julian R., Engel, Christoph ORCID: 0000-0002-7247-282X, Aretz, Stefan ORCID: 0000-0002-5228-1890, Jenkins, Mark A., Sunde, Lone ORCID: 0000-0002-8479-165X, Bernstein, Inge, Capella, Gabriel ORCID: 0000-0002-4669-7320, Balaguer, Francesc ORCID: 0000-0002-0206-0539, Macrae, Finlay, Winship, Ingrid M., Thomas, Huw, Evans, Dafydd Gareth, Burn, John, Greenblatt, Marc, Cappel, Wouter H. de Vos Tot Nederveen, Sijmons, Rolf H., Nielsen, Maartje, Bertario, Lucio, Bonanni, Bernardo, Tibiletti, Maria Grazia, Cavestro, Giulia Martina, Lindblom, Annika, Della Valle, Adriana, Lopez-Kostner, Francisco, Alvarez, Karin, Gluck, Nathan, Katz, Lior, Heinimann, Karl, Vaccaro, Carlos A., Nakken, Sigve ORCID: 0000-0001-8468-2050, Hovig, Eivind ORCID: 0000-0002-9103-1077, Green, Kate, Lalloo, Fiona, Hill, James, Vasen, Hans F. A., Perne, Claudia, Buettner, Reinhard, Goergens, Heike, Holinski-Feder, Elke, Morak, Monika, Holzapfel, Stefanie, Hueneburg, Robert, Doeberitz, Magnus von Knebel, Loeffler, Markus, Rahner, Nils, Weitz, Juergen, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak ORCID: 0000-0002-4175-5683, Crosbie, Emma J., Pineda, Marta, Navarro, Matilde, Brunet, Joan, Moreira, Leticia ORCID: 0000-0002-4518-8591, Sanchez, Ariadna ORCID: 0000-0003-0409-1328, Serra-Burriel, Miquel ORCID: 0000-0001-8595-1224, Mints, Miriam, Kariv, Revital, Rosner, Guy, Pinero, Tamara Alejandra, Pavicic, Walter Hernan, Kalfayan, Pablo, ten Broeke, Sanne W., Mecklin, Jukka-Pekka, Pylvanainen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Peltomaki, Paivi ORCID: 0000-0001-8819-2980, Hopper, John L., Win, Aung Ko, Buchanan, Daniel D., Lindor, Noralane M., Gallinger, Steven, Le Marchand, Loic, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Therkildsen, Christina, Hansen, Thomas V. O., Lindberg, Lars, Rodland, Einar Andreas, Neffa, Florencia, Esperon, Patricia, Tjandra, Douglas, Moslein, Gabriela, Seppala, Toni T. and Moller, Pal (2021). No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study. J. Clin. Med., 10 (13). BASEL: MDPI. ISSN 2077-0383

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dominguez-Valentin, MevUNSPECIFIEDorcid.org/0000-0001-7856-0057UNSPECIFIED
Plazzer, John-PaulUNSPECIFIEDorcid.org/0000-0001-5114-4301UNSPECIFIED
Sampson, Julian R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
Aretz, StefanUNSPECIFIEDorcid.org/0000-0002-5228-1890UNSPECIFIED
Jenkins, Mark A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sunde, LoneUNSPECIFIEDorcid.org/0000-0002-8479-165XUNSPECIFIED
Bernstein, IngeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Capella, GabrielUNSPECIFIEDorcid.org/0000-0002-4669-7320UNSPECIFIED
Balaguer, FrancescUNSPECIFIEDorcid.org/0000-0002-0206-0539UNSPECIFIED
Macrae, FinlayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winship, Ingrid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, HuwUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, Dafydd GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burn, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greenblatt, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cappel, Wouter H. de Vos Tot NederveenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sijmons, Rolf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, MaartjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertario, LucioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonanni, BernardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tibiletti, Maria GraziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cavestro, Giulia MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindblom, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Della Valle, AdrianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Kostner, FranciscoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alvarez, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gluck, NathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Katz, LiorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinimann, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaccaro, Carlos A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakken, SigveUNSPECIFIEDorcid.org/0000-0001-8468-2050UNSPECIFIED
Hovig, EivindUNSPECIFIEDorcid.org/0000-0002-9103-1077UNSPECIFIED
Green, KateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lalloo, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hill, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vasen, Hans F. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perne, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goergens, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holinski-Feder, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morak, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzapfel, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hueneburg, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doeberitz, Magnus von KnebelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loeffler, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahner, NilsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weitz, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinke-Lange, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmiegel, WolffUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vangala, DeepakUNSPECIFIEDorcid.org/0000-0002-4175-5683UNSPECIFIED
Crosbie, Emma J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pineda, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Navarro, MatildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunet, JoanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreira, LeticiaUNSPECIFIEDorcid.org/0000-0002-4518-8591UNSPECIFIED
Sanchez, AriadnaUNSPECIFIEDorcid.org/0000-0003-0409-1328UNSPECIFIED
Serra-Burriel, MiquelUNSPECIFIEDorcid.org/0000-0001-8595-1224UNSPECIFIED
Mints, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kariv, RevitalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosner, GuyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pinero, Tamara AlejandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pavicic, Walter HernanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalfayan, PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
ten Broeke, Sanne W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mecklin, Jukka-PekkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pylvanainen, KirsiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renkonen-Sinisalo, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lepisto, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peltomaki, PaiviUNSPECIFIEDorcid.org/0000-0001-8819-2980UNSPECIFIED
Hopper, John L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Win, Aung KoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buchanan, Daniel D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindor, Noralane M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallinger, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Marchand, LoicUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Newcomb, Polly A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueiredo, Jane C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thibodeau, Stephen N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Therkildsen, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Thomas V. O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindberg, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodland, Einar AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neffa, FlorenciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esperon, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tjandra, DouglasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moslein, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seppala, Toni T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, PalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-608148
DOI: 10.3390/jcm10132856
Journal or Publication Title: J. Clin. Med.
Volume: 10
Number: 13
Date: 2021
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2077-0383
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MISMATCH REPAIR GENES; CANCER-RISK; MUTATIONS; MISSENSE; 11Q23.1; 8Q23.3; HMSH2; AGEMultiple languages
Medicine, General & InternalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60814

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