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Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

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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 …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.

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

Date Published: 1st Dec 2022

Publication Type: Journal

Is HLA type a possible cancer risk modifier in Lynch syndrome?

Abstract

Not specified

Authors: Aysel Ahadova, Johannes Witt, Saskia Haupt, Richard Gallon, Robert Hüneburg, Jacob Nattermann, Sanne ten Broeke, Lena Bohaumilitzky, Alejandro Hernandez‐Sanchez, Mauro Santibanez‐Koref, Michael S. Jackson, Maarit Ahtiainen, Kirsi Pylvänäinen, Katarina Andini, Vince Kornel Grolmusz, Gabriela Möslein, Mev Dominguez‐Valentin, Pål Møller, Daniel Fürst, Rolf Sijmons, Gillian M. Borthwick, John Burn, Jukka‐Pekka Mecklin, Vincent Heuveline, Magnus von Knebel Doeberitz, Toni Seppälä, Matthias Kloor

Date Published: 14th Oct 2022

Publication Type: Journal

Opportunities and challenges in machine learning‐based newborn screening—A systematic literature review

Abstract

Not specified

Authors: Elaine Zaunseder, Saskia Haupt, Ulrike Mütze, Sven F. Garbade, Stefan Kölker, Vincent Heuveline

Date Published: 1st May 2022

Publication Type: Journal

A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis

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Abstract Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the … DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra-crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic CTNNB1 mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes APC and CTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The in silico experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.

Authors: Saskia Haupt, Nils Gleim, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline

Date Published: 4th Jul 2021

Publication Type: Journal

Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure

Abstract (Expand)

Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common … inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.

Authors: Saskia Haupt, Alexander Zeilmann, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline

Date Published: 1st May 2021

Publication Type: Journal

Computational model investigates the evolution of colonic crypts during Lynch syndrome carcinogenesis

Abstract

Not specified

Authors: Saskia Haupt, Nils Gleim, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline

Date Published: 29th Dec 2020

Publication Type: Unpublished

The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

Abstract

Not specified

Authors: Alexej Ballhausen, Moritz Jakob Przybilla, Michael Jendrusch, Saskia Haupt, Elisabeth Pfaffendorf, Florian Seidler, Johannes Witt, Alejandro Hernandez Sanchez, Katharina Urban, Markus Draxlbauer, Sonja Krausert, Aysel Ahadova, Martin Simon Kalteis, Pauline L. Pfuderer, Daniel Heid, Damian Stichel, Johannes Gebert, Maria Bonsack, Sarah Schott, Hendrik Bläker, Toni Seppälä, Jukka-Pekka Mecklin, Sanne Ten Broeke, Maartje Nielsen, Vincent Heuveline, Julia Krzykalla, Axel Benner, Angelika Beate Riemer, Magnus von Knebel Doeberitz, Matthias Kloor

Date Published: 1st Dec 2020

Publication Type: Journal

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