Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
Authors: Møller Pål , Seppälä Toni , Dowty James G. , Haupt Saskia , Dominguez-Valentin Mev , Sunde Lone , Bernstein Inge , Engel Christoph , Aretz Stefan , Nielsen Maartje , Capella Gabriel , Evans Dafydd Gareth , Burn John , Holinski-Feder Elke , Bertario Lucio , Bonanni Bernardo , Lindblom Annika , Levi Zohar , Macrae Finlay , Winship Ingrid , Plazzer John-Paul , Sijmons Rolf , Laghi Luigi , Valle Adriana Della , Heinimann Karl , Half Elizabeth , Lopez-Koestner Francisco , Alvarez-Valenzuela Karin , Scott Rodney J. , Katz Lior , Laish Ido , Vainer Elez , Vaccaro Carlos Alberto , Carraro Dirce Maria , Gluck Nathan , Abu-Freha Naim , Stakelum Aine , Kennelly Rory , Winter Des , Rossi Benedito Mauro , Greenblatt Marc , Bohorquez Mabel , Sheth Harsh , Tibiletti Maria Grazia , Lino-Silva Leonardo S. , Horisberger Karoline , Portenkirchner Carmen , Nascimento Ivana , Rossi Norma Teresa , da Silva Leandro Apolinário , Thomas Huw , Zaránd Attila , Mecklin Jukka-Pekka , Pylvänäinen Kirsi , Renkonen-Sinisalo Laura , Lepisto Anna , Peltomäki Päivi , Therkildsen Christina , Lindberg Lars Joachim , Thorlacius-Ussing Ole , von Knebel Doeberitz Magnus , Loeffler Markus , Rahner Nils , Steinke-Lange Verena , Schmiegel Wolff , Vangala Deepak , Perne Claudia , Hüneburg Robert , de Vargas Aída Falcón , Latchford Andrew , Gerdes Anne-Marie , Backman Ann-Sofie , Guillén-Ponce Carmen , Snyder Carrie , Lautrup Charlotte K. , Amor David , Palmero Edenir , Stoffel Elena , Duijkers Floor , Hall Michael J. , Hampel Heather , Williams Heinric , Okkels Henrik , Lubiński Jan , Reece Jeanette , Ngeow Joanne , Guillem Jose G. , Arnold Julie , Wadt Karin , Monahan Kevin , Senter Leigha , Rasmussen Lene J. , van Hest Liselotte P. , Ricciardiello Luigi , Kohonen-Corish Maija R. J. , Ligtenberg Marjolijn J. L. , Southey Melissa , Aronson Melyssa , Zahary Mohd N. , Samadder N. Jewel , Poplawski Nicola , Hoogerbrugge Nicoline , Morrison Patrick J. , James Paul , Lee Grant , Chen-Shtoyerman Rakefet , Ankathil Ravindran , Pai Rish , Ward Robyn , Parry Susan , Dębniak Tadeusz , John Thomas , van Overeem Hansen Thomas , Caldés Trinidad , Yamaguchi Tatsuro , Barca-Tierno Verónica , Garre Pilar , Cavestro Giulia Martina , Weitz Jürgen , Redler Silke , Büttner Reinhard , Heuveline Vincent , Hopper John L. , Win Aung Ko , Lindor Noralane , Gallinger Steven , Le Marchand Loïc , Newcomb Polly A. , Figueiredo Jane , Buchanan Daniel D. , Thibodeau Stephen N. , ten Broeke Sanne W. , Hovig Eivind , Nakken Sigve , Pineda Marta , Dueñas Nuria , Brunet Joan , Green Kate , Lalloo Fiona , Newton Katie , Crosbie Emma J. , Mints Miriam , Tjandra Douglas , Neffa Florencia , Esperon Patricia , Kariv Revital , Rosner Guy , Pavicic Walter Hernán , Kalfayan Pablo , Torrezan Giovana Tardin , Bassaneze Thiago , Martin Claudia , Moslein Gabriela , Ahadova Aysel , Kloor Matthias , Sampson Julian R. , Jenkins Mark A. ,   The European Hereditary Tumour Group (EHTG) and the International Mismatch Repair Consortium (IMRC)
Published: October 2022

Objective

To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants.

Methods

CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands.

Results

In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups.

Conclusions

Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.