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17 Publications visible to you, out of a total of 17
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

Abstract (Expand)

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

Age‐dependent performance of BRAF mutation testing in Lynch syndrome diagnostics

Abstract

Not specified

Authors: Hendrik Bläker, Saskia Haupt, Monika Morak, Elke Holinski‐Feder, Alexander Arnold, David Horst, Julia Sieber‐Frank, Florian Seidler, Moritz Winterfeld, Elizabeth Alwers, Jenny Chang‐Claude, Hermann Brenner, Wilfried Roth, Christoph Engel, Markus Löffler, Gabriela Möslein, Hans‐Konrad Schackert, Jürgen Weitz, Claudia Perne, Stefan Aretz, Robert Hüneburg, Wolff Schmiegel, Deepak Vangala, Nils Rahner, Verena Steinke‐Lange, Vincent Heuveline, Magnus von Knebel Doeberitz, Aysel Ahadova, Michael Hoffmeister, Matthias Kloor

Date Published: 15th Nov 2020

Publication Type: Journal

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