Abstract
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.
| Original language | English |
|---|---|
| Article number | 36 |
| Number of pages | 11 |
| Journal | Hereditary Cancer in Clinical Practice |
| Volume | 20 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Oct 2022 |
Keywords
- Colonoscopy
- Colorectal cancer
- Epidemiology
- Incidence
- Lynch Syndrome
- Over-diagnosis
- Penetrance
- Prevention
- Prospective
- Segregation analysis
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In: Hereditary Cancer in Clinical Practice, Vol. 20, No. 1, 36, 01.10.2022.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Colorectal cancer incidences in Lynch syndrome
T2 - a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
AU - Møller, Pål
AU - Seppälä, Toni
AU - Dowty, James G.
AU - Haupt, Saskia
AU - Dominguez-Valentin, Mev
AU - Sunde, Lone
AU - Bernstein, Inge
AU - Engel, Christoph
AU - Aretz, Stefan
AU - Nielsen, Maartje
AU - Capella, Gabriel
AU - Evans, Dafydd Gareth
AU - Burn, John
AU - Holinski-Feder, Elke
AU - Bertario, Lucio
AU - Bonanni, Bernardo
AU - Lindblom, Annika
AU - Levi, Zohar
AU - Macrae, Finlay
AU - Winship, Ingrid
AU - Plazzer, John Paul
AU - Sijmons, Rolf
AU - Laghi, Luigi
AU - Valle, Adriana Della
AU - Heinimann, Karl
AU - Half, Elizabeth
AU - Lopez-Koestner, Francisco
AU - Alvarez-Valenzuela, Karin
AU - Scott, Rodney J.
AU - Katz, Lior
AU - Laish, Ido
AU - Vainer, Elez
AU - Vaccaro, Carlos Alberto
AU - Carraro, Dirce Maria
AU - Gluck, Nathan
AU - Abu-Freha, Naim
AU - Stakelum, Aine
AU - Kennelly, Rory
AU - Winter, Des
AU - Rossi, Benedito Mauro
AU - Greenblatt, Marc
AU - Bohorquez, Mabel
AU - Sheth, Harsh
AU - Tibiletti, Maria Grazia
AU - Lino-Silva, Leonardo S.
AU - Horisberger, Karoline
AU - Portenkirchner, Carmen
AU - Nascimento, Ivana
AU - Rossi, Norma Teresa
AU - da Silva, Leandro Apolinário
AU - Thomas, Huw
AU - Zaránd, Attila
AU - Mecklin, Jukka Pekka
AU - Pylvänäinen, Kirsi
AU - Renkonen-Sinisalo, Laura
AU - Lepisto, Anna
AU - Peltomäki, Päivi
AU - Therkildsen, Christina
AU - Lindberg, Lars Joachim
AU - Thorlacius-Ussing, Ole
AU - von Knebel Doeberitz, Magnus
AU - Loeffler, Markus
AU - Rahner, Nils
AU - Steinke-Lange, Verena
AU - Schmiegel, Wolff
AU - Vangala, Deepak
AU - Perne, Claudia
AU - Hüneburg, Robert
AU - de Vargas, Aída Falcón
AU - Latchford, Andrew
AU - Gerdes, Anne Marie
AU - Backman, Ann Sofie
AU - Guillén-Ponce, Carmen
AU - Snyder, Carrie
AU - Lautrup, Charlotte K.
AU - Amor, David
AU - Palmero, Edenir
AU - Stoffel, Elena
AU - Duijkers, Floor
AU - Hall, Michael J.
AU - Hampel, Heather
AU - Williams, Heinric
AU - Okkels, Henrik
AU - Lubiński, Jan
AU - Reece, Jeanette
AU - Ngeow, Joanne
AU - Guillem, Jose G.
AU - Arnold, Julie
AU - Wadt, Karin
AU - Monahan, Kevin
AU - Senter, Leigha
AU - Rasmussen, Lene J.
AU - van Hest, Liselotte P.
AU - Ricciardiello, Luigi
AU - Kohonen-Corish, Maija R.J.
AU - Ligtenberg, Marjolijn J.L.
AU - Southey, Melissa
AU - Aronson, Melyssa
AU - Zahary, Mohd N.
AU - Samadder, N. Jewel
AU - Poplawski, Nicola
AU - Hoogerbrugge, Nicoline
AU - Morrison, Patrick J.
AU - James, Paul
AU - Lee, Grant
AU - Chen-Shtoyerman, Rakefet
AU - Ankathil, Ravindran
AU - Pai, Rish
AU - Ward, Robyn
AU - Parry, Susan
AU - Dębniak, Tadeusz
AU - John, Thomas
AU - van Overeem Hansen, Thomas
AU - Caldés, Trinidad
AU - Yamaguchi, Tatsuro
AU - Barca-Tierno, Verónica
AU - Garre, Pilar
AU - Cavestro, Giulia Martina
AU - Weitz, Jürgen
AU - Redler, Silke
AU - Büttner, Reinhard
AU - Heuveline, Vincent
AU - Hopper, John L.
AU - Win, Aung Ko
AU - Lindor, Noralane
AU - Gallinger, Steven
AU - Le Marchand, Loïc
AU - Newcomb, Polly A.
AU - Figueiredo, Jane
AU - Buchanan, Daniel D.
AU - Thibodeau, Stephen N.
AU - ten Broeke, Sanne W.
AU - Hovig, Eivind
AU - Nakken, Sigve
AU - Pineda, Marta
AU - Dueñas, Nuria
AU - Brunet, Joan
AU - Green, Kate
AU - Lalloo, Fiona
AU - Newton, Katie
AU - Crosbie, Emma J.
AU - Mints, Miriam
AU - Tjandra, Douglas
AU - Neffa, Florencia
AU - Esperon, Patricia
AU - Kariv, Revital
AU - Rosner, Guy
AU - Pavicic, Walter Hernán
AU - Kalfayan, Pablo
AU - Torrezan, Giovana Tardin
AU - Bassaneze, Thiago
AU - Martin, Claudia
AU - Moslein, Gabriela
AU - Ahadova, Aysel
AU - Kloor, Matthias
AU - Sampson, Julian R.
AU - Jenkins, Mark A.
AU - The European Hereditary Tumour Group (EHTG)
AU - the International Mismatch Repair Consortium (IMRC)
N1 - Funding Information: Toni T. Seppälä: Finnish Medical Foundation, Emil Aaltonen Foundation, Cancer Society Finland, Jane and Aatos Erkko Foundation, iCAN Digital Precision Cancer Medicine Flagship, Relander Foundation, Sigrid Juselius Foundation, and Academy of Finland. Jukka-Pekka Mecklin: Cancer Society Finland, Jane and Aatos Erkko Foundation. G Capellá team: funded by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds -a way to build Europe- (grant PID2019-111254RB-I00) and CIBERONC (CB16/12/00234). We thank CERCA Program / Generalitat de Catalunya for institutional support. S Aretz , E Holinski-Feder, and V Steinke-Lange were supported by the European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) – Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016 – Framework Partnership Agreement 2017–2021”. BMRossi team: we thank LA-GETH (Latin America - Grupo de Estudios de Tumores Hereditarios) for the Institutional support. DGE and EJC are supported by the all Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). JRS thanks HCRW for its support via Wales Gene Park. MRJ Kohonen-Corish had a grant from Cancer Council NSW grant RG19-01. J Burn contributed with support from Cancer Research U.K. catalyst award: Aspirin for Cancer Prevention AsCaP CRUK A24991. ”. The German Consortium for Familial Intestinal Cancer was supported by grants of the German Cancer Aid. DM Carraro and GT Torrezan: Funded by the National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (FAPESP 2014/509443-1, CNPq 465682/2014-6 and CAPES - 88887.136405/2017-00). ). We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017. Funding Information: Harsh Sheth contributed with support from Gujarat State Biotechnology Mission grant GSBTM/JD(R&D)/604/2018-2019/7 and clinical oncologists Prof. Suresh h Advani, Dr. Pankaj Shah and Dr. Abhinav Jain. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016 – Framework Partnership Agreement 2017–2021”. Funding bodies had no role in the study design, collection, analysis or interpretation of the data. Publisher Copyright: © 2022, The Author(s).
PY - 2022/10/1
Y1 - 2022/10/1
N2 - 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.
AB - 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.
KW - Colonoscopy
KW - Colorectal cancer
KW - Epidemiology
KW - Incidence
KW - Lynch Syndrome
KW - Over-diagnosis
KW - Penetrance
KW - Prevention
KW - Prospective
KW - Segregation analysis
UR - http://www.scopus.com/inward/record.url?scp=85139440044&partnerID=8YFLogxK
U2 - 10.1186/s13053-022-00241-1
DO - 10.1186/s13053-022-00241-1
M3 - Article
C2 - 36182917
AN - SCOPUS:85139440044
SN - 1731-2302
VL - 20
JO - Hereditary Cancer in Clinical Practice
JF - Hereditary Cancer in Clinical Practice
IS - 1
M1 - 36
ER -