Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Mev Dominguez-Valentin; Julian R Sampson; Toni T Seppala; Sanne W ten Broeke; John-Paul Plazzer; Sigve Nakken; Christoph Engel; Stefan Aretz; Mark A Jenkins; Lone Sunde; Inge Bernstein; Gabriel Capella; Francesc Balaguer; Huw Thomas; D Gareth Evans; John Burn; Marc Greenblatt; Eivind Hovig; Wouter H de Vos Tot Nederveen Cappel; Rolf H Sijmons; Lucio Bertario; Maria Grazia Tibiletti; Giulia Martina Cavestro; Annika Lindblom; Adriana Della Valle; Francisco Lopez-Kostner; Nathan Gluck; Lior H Katz; Karl Heinimann; Carlos A Vaccaro; Reinhard Buettner; Heike Goergens; Elke Holinski-Feder; Monika Morak; Stefanie Holzapfel; Robert Hueneburg; Magnus von Knebel Doeberitz; Markus Loeffler; Nils Rahner; Hans K Schackert; Verena Steinke-Lange; Wolff Schmiegel; Deepak Vangala; Kirsi Pylvanainen; Laura Renkonen-Sinisalo; John L Hopper; Aung Ko Win; Robert W Haile; Noralane M Lindor; Steven Gallinger; Loic Le Marchand; Polly A Newcomb; Jane C Figueiredo; Stephen N Thibodeau; Karin Wadt; Christina Therkildsen; Henrik Okkels; Zohreh Ketabi; Leticia Moreira; Ariadna Sanchez; Miquel Serra-Burriel; Marta Pineda; Matilde Navarro; Ignacio Blanco; Kate Green; Fiona Lalloo; Emma J Crosbie; James Hill; Oliver G Denton; Ian M Frayling; Einar Andreas Rodland; Hans Vasen; Miriam Mints; Florencia Neffa; Patricia Esperon; Karin Alvarez; Revital Kariv; Guy Rosner; Tamara Alejandra Pinero; Maria Laura Gonzalez; Pablo Kalfayan; Douglas Tjandra; Ingrid M Winship; Finlay Macrae; Gabriela Moeslein; Jukka-Pekka Mecklin; Maartje Nielsen; Pal Moller

Journal article

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Mev Dominguez-Valentin, Julian R Sampson, Toni T Seppala, Sanne W ten Broeke, John-Paul Plazzer, Sigve Nakken, Christoph Engel, Stefan Aretz, Mark A Jenkins, Lone Sunde, Inge Bernstein, Gabriel Capella, Francesc Balaguer, Huw Thomas, D Gareth Evans, John Burn, Marc Greenblatt, Eivind Hovig, Wouter H de Vos Tot Nederveen Cappel, Rolf H Sijmons Show all

GENETICS IN MEDICINE | ELSEVIER SCIENCE INC | Published : 2020

DOI: 10.1038/s41436-019-0596-9

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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 s..

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University of Melbourne Researchers

John Hopper Author Melbourne School of Population and Global Health

Aung Ko Win Author Melbourne School of Population and Global Health

Ingrid Winship Author Medicine - Royal Melbourne Hospital

Mark Jenkins Author Melbourne School of Population and Global Health

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Grants

Awarded by Norwegian Cancer Society

Awarded by Manchester National Institute for Health Research (NIHR) Biomedical Research Centre

Awarded by National Cancer Institute of the National Institutes of Health

Awarded by Colorectal Cancer Family Registry (CCFR) center: Australasian Colorectal Cancer Family Registry (National Cancer Institute/National Institutes of Health [NCI/NIH])

Awarded by Colorectal Cancer Family Registry (CCFR) center: Mayo Clinic Cooperative Family Registry for Colon Cancer Studies

Awarded by Colorectal Cancer Family Registry (CCFR) center: Ontario Familial Colorectal Cancer Registry

Awarded by Colorectal Cancer Family Registry (CCFR) center: Seattle Colorectal Cancer Family Registry

Awarded by Colorectal Cancer Family Registry (CCFR) center: University of Hawaii Colorectal Cancer Family Registry

Awarded by Colorectal Cancer Family Registry (CCFR) center: University of Southern California (USC) Consortium Colorectal Cancer Family Registry

Awarded by FEDER funds -a way to build Europe

Awarded by Government of Catalonia

Awarded by Instituto de Salud Carlos III

Funding Acknowledgements

We express our gratitude to Heikki Jarvinen, Anna Lepisto, Beatriz Alcala-Repo, Teresa Ocana, Maria Pellise, Sabela Carballal, Liseth Rivero, Lorena Moreno, Gerhard Jung, Antoni Castells, Joaquin Cubiella, Laura Rivas, Luis Bujanda, Ines Gil, Jesus Banales, Catalina Garau, Rodrigo Jover, Maria Dolores Pico, Xavier Bessa, Cristina Alvarez, Montserrat Andreu, Carmen Poves, Pedro Perez Segura, Lucia Cid, Marta Carrillo, Enrique Quintero, Angeles Pizarro, Marta Garzon, Adolfo Suarez, Inmaculada Salces, Daniel Rodriguez-Alcalde, Judith Balmana, Adria Lopez, Nuria Duenas, Gemma Llort, Carmen Yague, Teresa Ramon i Cajal, David Fisas Masferrer, Alexandra Gisbert Beamud, Consol Lopez San Martin, Maite Herraiz, Pilar Perez, Cristina Carretero, Maite Betes, 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 Asociacion Espanola de Gastroenterologia (AEG). Data collection from Wales, UK was supported by the Wales Gene Park. This work was cofunded by the European Regional Development Fund (ERDF).