Curriculum vitae

@misc{Haupt2023Mathematical,
	author = {Haupt, Saskia},
	year = {2023},
	month = {apr 19},
	school = {Heidelberg University Library},
	title = {Mathematical modeling of {Lynch} syndrome carcinogenesis},
}

@thesis{Haupt2023Mathematical,
	abstract = {\textless{}jats:p\textgreater{} Cancer is one of the leading causes of disease-related death worldwide. In recent years, large amounts of data on cancer genetics and molecular characteristics have become available and accumulated with increasing speed. However, the current understanding of cancer as a disease is still limited by the lack of suitable models that allow interpreting these data in proper ways. Thus, the highly interdisciplinary research field of mathematical oncology has evolved to use mathematics, modeling, and simulations to study cancer with the overall goal to improve clinical patient care. This dissertation aims at developing mathematical models and tools for different spatial scales of cancer development at the example of colorectal cancer in Lynch syndrome, the most common inherited colorectal cancer predisposition syndrome. We derive model-driven approaches for carcinogenesis at the DNA, cell, and crypt level, as well as data-driven methods for cancer-immune interactions at the DNA level and for the evaluation of diagnostic procedures at the Lynch syndrome population level. The developed models present an important step toward an improved understanding of hereditary cancer as a disease aiming at rapid implementation into clinical management guidelines and into the development of novel, innovative approaches for prevention and treatment.\textless{}/jats:p\textgreater{}},
	author = {Haupt, Saskia},
	booktitle = {Heidelberg {University} {Library}},
	doi = {10.11588/HEIDOK.00033194},
	date = {2023-04-19},
	institution = {Heidelberg University Library},
	title = {Mathematical modeling of {Lynch} syndrome carcinogenesis},
	url = {https://archiv.ub.uni-heidelberg.de/volltextserver/id/eprint/33194},
}

@article{Haupt2021computational,
	author = {Haupt, Saskia and Gleim, Nils and Ahadova, Aysel and Bl{\" a}ker, Hendrik and Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
	journal = {Computational and Systems Oncology},
	number = {2},
	year = {2021},
	month = {jun 21},
	publisher = {Wiley},
	title = {A computational model for investigating the evolution of colonic crypts during {Lynch} syndrome carcinogenesis},
	volume = {1},
}

@article{Haupt2021computational,
	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 \textit{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 \textit{APC} and \textit{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 \textit{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.},
	author = {Haupt, Saskia and Gleim, Nils and Ahadova, Aysel and Bl{\" a}ker, Hendrik and Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
	journaltitle = {Computational and Systems Oncology},
	shortjournal = {Comp Sys Onco},
	doi = {10.1002/cso2.1020},
	issn = {2689-9655},
	number = {2},
	date = {2021-06-21},
	language = {en},
	publisher = {Wiley},
	title = {A computational model for investigating the evolution of colonic crypts during {Lynch} syndrome carcinogenesis},
	url = {http://dx.doi.org/10.1002/cso2.1020},
	volume = {1},
}

@article{Haupt2021Mathematical,
	author = {Haupt, Saskia and Zeilmann, Alexander and Ahadova, Aysel and Bl{\" a}ker, Hendrik and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
	journal = {PLOS Computational Biology},
	editor = {Chen, Jing},
	number = {5},
	year = {2021},
	month = {may 18},
	pages = {e1008970},
	publisher = {Public Library of Science (PLoS)},
	title = {Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with {Kronecker} structure},
	volume = {17},
}

@article{Haupt2021Mathematical,
	abstract = {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 \textit{APC}, \textit{CTNNB1}, \textit{KRAS} and \textit{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 \textit{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 \textit{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.},
	author = {Haupt, Saskia and Zeilmann, Alexander and Ahadova, Aysel and Bl{\" a}ker, Hendrik and von Knebel Doeberitz, Magnus and Kloor, Matthias and Heuveline, Vincent},
	journaltitle = {PLOS Computational Biology},
	shortjournal = {PLoS Comput Biol},
	doi = {10.1371/journal.pcbi.1008970},
	editor = {Chen, Jing},
	issn = {1553-7358},
	number = {5},
	date = {2021-05-18},
	language = {en},
	pages = {e1008970},
	eid = {e1008970},
	eprint = {34003820},
	eprinttype = {pubmed},
	publisher = {Public Library of Science (PLoS)},
	title = {Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with {Kronecker} structure},
	url = {http://dx.doi.org/10.1371/journal.pcbi.1008970},
	volume = {17},
}