Title
Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database
Date Issued
01 January 2020
Access level
open access
Resource Type
journal article
Author(s)
Sampson J.R.
Seppälä T.T.
ten Broeke S.W.
Plazzer J.P.
Nakken S.
Engel C.
Aretz S.
Jenkins M.A.
Sunde L.
Bernstein I.
Capella G.
Balaguer F.
Thomas H.
Evans D.G.
Burn J.
Greenblatt M.
Hovig E.
de Vos tot Nederveen Cappel W.H.
Sijmons R.H.
Bertario L.
Tibiletti M.G.
Cavestro G.M.
Lindblom A.
Della Valle A.
Lopez-Köstner F.
Gluck N.
Katz L.H.
Heinimann K.
Vaccaro C.A.
Büttner R.
Görgens H.
Holinski-Feder E.
Morak M.
Holzapfel S.
Hüneburg R.
Knebel Doeberitz M.v.
Loeffler M.
Rahner N.
Schackert H.K.
Steinke-Lange V.
Schmiegel W.
Vangala D.
Pylvänäinen K.
Renkonen-Sinisalo L.
Hopper J.L.
Win A.K.
Haile R.W.
Lindor N.M.
Gallinger S.
Le Marchand L.
Newcomb P.A.
Figueiredo J.C.
Thibodeau S.N.
Wadt K.
Therkildsen C.
Okkels H.
Ketabi Z.
Moreira L.
Sánchez A.
Serra-Burriel M.
Pineda M.
Navarro M.
Blanco I.
Green K.
Lalloo F.
Crosbie E.J.
Hill J.
Denton O.G.
Frayling I.M.
Rødland E.A.
Vasen H.
Mints M.
Neffa F.
Esperon P.
Alvarez K.
Kariv R.
Rosner G.
Pinero T.A.
Gonzalez M.L.
Kalfayan P.
Tjandra D.
Winship I.M.
Macrae F.
Möslein G.
Mecklin J.P.
Nielsen M.
Møller P.
Oslo University Hospital
Publisher(s)
Springer Nature
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.
Start page
15
End page
25
Volume
22
Issue
1
Language
English
OCDE Knowledge area
Genética humana
Subjects
Scopus EID
2-s2.0-85069746674
PubMed ID
Source
Genetics in Medicine
ISSN of the container
10983600
Sponsor(s)
We express our gratitude to Heikki Järvinen, Anna Lepistö, Beatriz Alcala-Repo, Teresa Ocaña, María Pellisé, Sabela Carballal, Liseth Rivero, Lorena Moreno, Gerhard Jung, Antoni Castells, Joaquin Cubiella, Laura Rivas, Luis Bujanda, Inés Gil, Jesús Bañales, Catalina Garau, Rodrigo Jover, María Dolores Picó, Xavier Bessa, Cristina Álvarez, Montserrat Andreu, Carmen Poves, Pedro Pérez Segura, Lucía Cid, Marta Carrillo, Enrique Quintero, Ángeles Pizarro, Marta Garzón, Adolfo Suárez, Inmaculada Salces, Daniel Rodriguez-Alcalde, Judith Balmaña, Adrià López, Nuria Dueñas, Gemma Llort, Carmen Yagüe, Teresa Ramón i Cajal, David Fisas Masferrer, Alexandra Gisbert Beamud, Consol López San Martín, Maite Herráiz, Pilar Pérez, Cristina Carretero, Maite Betés, Marta Ponce, Elena Aguirre, Nora Alfaro, Carlos Sarroca, and Marianne Haeusler for their efforts over the years. We also thank the Finnish Cancer Foundation, Jane and Aatos Erkko Foundation, and the Norwegian Cancer Society, contract 194751–2017 for funding. D.G.E. and E.J.C are supported by the all Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215–20007). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number UM1CA167551 and through cooperative agreements with the following Colorectal Cancer Family Registry (CCFR) centers: Australasian Colorectal Cancer Family Registry (National Cancer Institute/National Institutes of Health [NCI/NIH] U01 CA074778 and U01/U24 CA097735), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH U01/U24 CA074794), University of Hawaii Colorectal Cancer Family Registry (NCI/NIH U01/U24 CA074806 and R01 CA104132 to L.L.M.), University of Southern California (USC) Consortium Colorectal Cancer Family Registry (NCI/NIH U01/U24 CA074799). GC, MP and MN work was funded by the Spanish Ministry of Economy and Competitiveness and cofunded by FEDER funds -a way to build Europe-(grant SAF2015-68016-R), CIBERONC and the Government of Catalonia (grants 2017SGR1282 and PERIS SLT002/16/0037). The German Consortium for Familial Intestinal Cancer has been supported by grants from the German Cancer Aid. Data collection in Bonn was facilitated by the Center for Hereditary Tumor Syndromes, University of Bonn. F.B. is supported by grants from the Instituto de Salud Carlos III (PI13/00719; PI16/00766) and from the Asociación Española de Gastroenterología (AEG). Data collection from Wales, UK was supported by the Wales Gene Park. This work was cofunded by the European Regional Development Fund (ERDF).
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