Dominguez-Valentin, Mev ORCID: 0000-0001-7856-0057, Sampson, Julian R., Seppala, Toni T. ORCID: 0000-0002-4940-3498, ten Broeke, Sanne W., Plazzer, John-Paul, Nakken, Sigve ORCID: 0000-0001-8468-2050, Engel, Christoph ORCID: 0000-0002-7247-282X, Aretz, Stefan, Jenkins, Mark A., Sunde, Lone ORCID: 0000-0002-8479-165X, Bernstein, Inge ORCID: 0000-0003-4095-432X, Capella, Gabriel ORCID: 0000-0002-4669-7320, Balaguer, Francesc, Thomas, Huw, Evans, D. Gareth, Burn, John ORCID: 0000-0002-9823-2322, Greenblatt, Marc, Hovig, Eivind, de Vos Tot Nederveen Cappel, Wouter H., Sijmons, Rolf H., Bertario, Lucio, Tibiletti, Maria Grazia, Cavestro, Giulia Martina ORCID: 0000-0003-1947-9368, Lindblom, Annika, Della Valle, Adriana, Lopez-Kostner, Francisco, Gluck, Nathan, Katz, Lior H., Heinimann, Karl, Vaccaro, Carlos A., Buettner, Reinhard, Goergens, Heike, Holinski-Feder, Elke, Morak, Monika, Holzapfel, Stefanie, Hueneburg, Robert, von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Schackert, Hans K., Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Pylvanainen, Kirsi ORCID: 0000-0003-4399-9283, Renkonen-Sinisalo, Laura, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane M., Gallinger, Steven, Le Marchand, Loic, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Wadt, Karin, Therkildsen, Christina, Okkels, Henrik, Ketabi, Zohreh, Moreira, Leticia, Sanchez, Ariadna, Serra-Burriel, Miquel ORCID: 0000-0001-8595-1224, Pineda, Marta, Navarro, Matilde, Blanco, Ignacio ORCID: 0000-0002-7414-7481, Green, Kate, Lalloo, Fiona, Crosbie, Emma J., Hill, James, Denton, Oliver G., Frayling, Ian M., Rodland, Einar Andreas, Vasen, Hans, Mints, Miriam, Neffa, Florencia, Esperon, Patricia, Alvarez, Karin ORCID: 0000-0001-5349-0267, Kariv, Revital, Rosner, Guy, Pinero, Tamara Alejandra, Gonzalez, Maria Laura, Kalfayan, Pablo, Tjandra, Douglas, Winship, Ingrid M., Macrae, Finlay, Moeslein, Gabriela, Mecklin, Jukka-Pekka ORCID: 0000-0003-4895-2249, Nielsen, Maartje ORCID: 0000-0002-5351-1870 and Moller, Pal (2020). Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet. Med., 22 (1). S. 15 - 26. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1530-0366

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Abstract

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 to gene and gender and to determine survival after cancer. Methods We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. Results There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dominguez-Valentin, MevUNSPECIFIEDorcid.org/0000-0001-7856-0057UNSPECIFIED
Sampson, Julian R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seppala, Toni T.UNSPECIFIEDorcid.org/0000-0002-4940-3498UNSPECIFIED
ten Broeke, Sanne W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plazzer, John-PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakken, SigveUNSPECIFIEDorcid.org/0000-0001-8468-2050UNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
Aretz, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jenkins, Mark A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sunde, LoneUNSPECIFIEDorcid.org/0000-0002-8479-165XUNSPECIFIED
Bernstein, IngeUNSPECIFIEDorcid.org/0000-0003-4095-432XUNSPECIFIED
Capella, GabrielUNSPECIFIEDorcid.org/0000-0002-4669-7320UNSPECIFIED
Balaguer, FrancescUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, HuwUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, D. GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burn, JohnUNSPECIFIEDorcid.org/0000-0002-9823-2322UNSPECIFIED
Greenblatt, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hovig, EivindUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Vos Tot Nederveen Cappel, Wouter H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sijmons, Rolf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertario, LucioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tibiletti, Maria GraziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cavestro, Giulia MartinaUNSPECIFIEDorcid.org/0000-0003-1947-9368UNSPECIFIED
Lindblom, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Della Valle, AdrianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Kostner, FranciscoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gluck, NathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Katz, Lior H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinimann, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaccaro, Carlos A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goergens, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holinski-Feder, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morak, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzapfel, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hueneburg, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Knebel Doeberitz, MagnusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loeffler, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahner, NilsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schackert, Hans K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinke-Lange, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmiegel, WolffUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vangala, DeepakUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pylvanainen, KirsiUNSPECIFIEDorcid.org/0000-0003-4399-9283UNSPECIFIED
Renkonen-Sinisalo, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopper, John L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Win, Aung KoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haile, Robert W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindor, Noralane M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallinger, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Marchand, LoicUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Newcomb, Polly A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueiredo, Jane C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thibodeau, Stephen N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wadt, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Therkildsen, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okkels, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ketabi, ZohrehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreira, LeticiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez, AriadnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serra-Burriel, MiquelUNSPECIFIEDorcid.org/0000-0001-8595-1224UNSPECIFIED
Pineda, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Navarro, MatildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blanco, IgnacioUNSPECIFIEDorcid.org/0000-0002-7414-7481UNSPECIFIED
Green, KateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lalloo, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crosbie, Emma J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hill, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denton, Oliver G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frayling, Ian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodland, Einar AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vasen, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mints, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neffa, FlorenciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esperon, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alvarez, KarinUNSPECIFIEDorcid.org/0000-0001-5349-0267UNSPECIFIED
Kariv, RevitalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosner, GuyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pinero, Tamara AlejandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez, Maria LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalfayan, PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tjandra, DouglasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winship, Ingrid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Macrae, FinlayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moeslein, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mecklin, Jukka-PekkaUNSPECIFIEDorcid.org/0000-0003-4895-2249UNSPECIFIED
Nielsen, MaartjeUNSPECIFIEDorcid.org/0000-0002-5351-1870UNSPECIFIED
Moller, PalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-351747
DOI: 10.1038/s41436-019-0596-9
Journal or Publication Title: Genet. Med.
Volume: 22
Number: 1
Page Range: S. 15 - 26
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MUTATION CARRIERS; MLH1; MSH2Multiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/35174

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