Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study
2021; Elsevier BV; Volume: 22; Issue: 7 Linguagem: Inglês
10.1016/s1470-2045(21)00189-3
ISSN1474-5488
AutoresAung Ko Win, James G. Dowty, Jeanette C. Reece, Grant Lee, Allyson Templeton, John‐Paul Plazzer, Daniel D. Buchanan, Kiwamu Akagi, Seçil Ak Aksoy, Ángel Alonso, Karin Álvarez, David J. Amor, Ravindran Ankathil, Stefan Aretz, Julie Arnold, Melyssa Aronson, Rachel Austin, A Bäckman, Sanne W. ten Broeke, Verónica Barca-Tierno, Julian Barwell, Inge Bernstein, Pascaline Berthet, Beate Betz, Yves‐Jean Bignon, Talya Boisjoli, Valérie Bonadona, Laurent Briollais, Joan Brunet, Karolin Bucksch, Bruno Buecher, Reinhard Buettner, John Burn, Trinidad Caldés, Gabriel Capellá, Olivier Caron, Graham Casey, Min Hoe Chew, Yun‐Hee Choi, James M. Church, Mark Clendenning, Chrystelle Colas, Elisa J. Cops, Isabelle Coupier, Marcia Cruz‐Correa, Albert de la Chapelle, Niels de Wind, Tadeusz Dębniak, Adriana Della Valle, Capuccine Delnatte, Marion Dhooge, Mev Dominguez‐Valentin, Youenn Drouet, Floor A.M. Duijkers, Christoph Engel, Patricia Esperón, D. Gareth Evans, Aı́da Falcón de Vargas, Jane C. Figueiredo, William D. Foulkes, Emmanuelle Fourme, Thierry Frébourg, Steven Gallinger, Pilar Garré, Maurizio Genuardi, Anne–Marie Gerdes, Lauren M. Gima, Sophie Giraud, Annabel Goodwin, Heike Görgens, Kate Green, José G. Guillem, Carmen Guillén‐Ponce, Roselyne Guimbaud, Rodrigo Santa Cruz Guindalini, Elizabeth Half, Michael J. Hall, Heather Hampel, Thomas van Overeem Hansen, Karl Heinimann, Frederik J. Hes, James Hill, Judy Ho, Elke Holinski‐Feder, Nicoline Hoogerbrugge, Robert Hüneburg, Vanessa Huntley, Paul A. James, Uffe Birk Jensen, Thomas John, Wan Khairunnisa Wan Juhari, Matthew F. Kalady, Fay Kastrinos, Matthias Kloor, Maija Kohonen‐Corish, Lotte Krogh, Sonia S. Kupfer, Uri Ladabaum, Kristina Lagerstedt‐Robinson, Fiona Lalloo, Christine Lasset, Andrew Latchford, Pierre Laurent‐Puig, Charlotte Kvist Lautrup, Barbara Leggett, Sophie Lejeune, Loı̈c Le Marchand, Marjolijn J. L. Ligtenberg, Noralane M. Lindor, Markus Loeffler, Michel Longy, Francisco López, Jan T. Lowery, Jan Lubiński, Anneke Lucassen, Patrick M. Lynch, Karolina Malińska, Nagahide Matsubara, Jukka‐Pekka Mecklin, Pål Møller, Kevin Monahan, Patrick J. Morrison, Jacob Nattermann, Matilde Navarro, Florencia Neffa, Deborah W. Neklason, P A Newcomb, Joanne Ngeow, Cassandra Nichols, Maartje Nielsen, Dawn M. Nixon, Catherine Noguès, Henrik Okkels, Sylviane Olschwang, Nicholas Pachter, Rish K. Pai, Edenir Inêz Palmero, Mala Pande, Susan Parry, Swati Patel, Rachel Pearlman, Claudia Perne, Marta Pineda, Nicola Poplawski, Kirsi Pylvänäinen, Jay Qiu, Nils Rahner, Raj Ramesar, Lene Juel Rasmussen, Silke Redler, Rui Manuel Reis, Luigi Ricciardiello, Emilia Rogoża-Janiszewska, Christophe Rosty, N. Jewel Samadder, Julian R. Sampson, Hans K. Schackert, Wolff Schmiegel, Karsten Schulmann, Hélène Schuster, Rodney J. Scott, Leigha Senter, Toni T. Seppälä, Rakefet Chen‐Shtoyerman, Rolf H. Sijmons, Carrie Snyder, Ilana Solomon, José Luís Soto, Melissa C. Southey, Allan D. Spigelman, Florencia Spirandelli, Amanda B. Spurdle, Verena Steinke‐Lange, Elena M. Stoffel, Christian P. Strassburg, Lone Sunde, Rachel Susman, Sapna Syngal, Kohji Tanakaya, Gülçin Tezcan, Christina Therkildsen, S. N. Thibodeau, Naohiro Tomita, Katherine Tucker, Berrin Tunca, Daniela Turchetti, Nancy Uhrhammer, Joji Utsunomiya, Carlos Vaccaro, Fränzel J.B. van Duijnhoven, Meghan J. van Wanzeele, Deepak Vangala, Hans F. A. Vasen, Magnus von Knebel Doeberitz, Jenny von Salomé, Karin Wadt, Robyn L. Ward, Jürgen Weitz, Jeffrey N. Weitzel, Heinric Williams, Ingrid Winship, Paul E. Wise, Julie Wods, Michael O. Woods, Tatsuro Yamaguchi, Silke Zachariae, Mohd Nizam Zahary, John L. Hopper, Robert W. Haile, Finlay Macrae, Gabriela Möslein, Mark A. Jenkins,
Tópico(s)Colorectal Cancer Treatments and Studies
ResumoExisting clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence.In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%.Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome.National Health and Medical Research Council, Australia.
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