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. Seppälä, 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. SijmonsLucio Bertario, Maria Grazia Tibiletti, Giulia Martina Cavestro, Annika Lindblom, Adriana Della Valle, Francisco Lopez-Köstner, Nathan Gluck, Lior H. Katz, Karl Heinimann, Carlos A. Vaccaro, Reinhard Büttner, Heike Görgens, Elke Holinski-Feder, Monika Morak, Stefanie Holzapfel, Robert Hüneburg, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Hans K. Schackert, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, John L. Hopper, Aung Ko Win, Robert W. Haile, Noralane M. Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane C. Figueiredo, Stephen N. Thibodeau, Karin Wadt, Christina Therkildsen, Henrik Okkels, Zohreh Ketabi, Leticia Moreira, Ariadna Sánchez, 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 Rødland, Hans Vasen, Miriam Mints, Florencia Neffa, Patricia Esperon, Karin Alvarez, Revital Kariv, Guy Rosner, Tamara Alejandra Pinero, María Laura Gonzalez, Pablo Kalfayan, Douglas Tjandra, Ingrid M. Winship, Finlay Macrae, Gabriela Möslein, Jukka Pekka Mecklin, Maartje Nielsen, Pål Møller

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)15-25
Number of pages11
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 1 2020


  • Lynch syndrome
  • MLH1
  • MSH2
  • MSH6
  • PMS2

ASJC Scopus subject areas

  • Genetics(clinical)


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