Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

View ORCID ProfileSaskia Haupt, View ORCID ProfileNils Gleim, View ORCID ProfileAysel Ahadova, View ORCID ProfileHendrik Bläker, View ORCID ProfileMagnus von Knebel Doeberitz, View ORCID ProfileMatthias Kloor, View ORCID ProfileVincent Heuveline
doi: https://doi.org/10.1101/2020.12.29.424555
Saskia Haupt
1Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
2Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Saskia Haupt
  • For correspondence: saskia.haupt@uni-heidelberg.de
Nils Gleim
1Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nils Gleim
Aysel Ahadova
3Department of Applied Tumor Biology (ATB), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
4Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Aysel Ahadova
Hendrik Bläker
5Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hendrik Bläker
Magnus von Knebel Doeberitz
3Department of Applied Tumor Biology (ATB), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
4Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Magnus von Knebel Doeberitz
Matthias Kloor
3Department of Applied Tumor Biology (ATB), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
4Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthias Kloor
Vincent Heuveline
1Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
2Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Vincent Heuveline
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Data/Code
  • Preview PDF
Loading

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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding information The authors received no specific funding for this work.

  • https://github.com/Mathematics-in-Oncology/ComputationalColonicCrypts

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted July 06, 2021.
Download PDF
Data/Code
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis
Saskia Haupt, Nils Gleim, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline
bioRxiv 2020.12.29.424555; doi: https://doi.org/10.1101/2020.12.29.424555
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis
Saskia Haupt, Nils Gleim, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline
bioRxiv 2020.12.29.424555; doi: https://doi.org/10.1101/2020.12.29.424555

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4687)
  • Biochemistry (10371)
  • Bioengineering (7690)
  • Bioinformatics (26364)
  • Biophysics (13545)
  • Cancer Biology (10716)
  • Cell Biology (15457)
  • Clinical Trials (138)
  • Developmental Biology (8509)
  • Ecology (12837)
  • Epidemiology (2067)
  • Evolutionary Biology (16880)
  • Genetics (11409)
  • Genomics (15489)
  • Immunology (10633)
  • Microbiology (25243)
  • Molecular Biology (10234)
  • Neuroscience (54571)
  • Paleontology (402)
  • Pathology (1671)
  • Pharmacology and Toxicology (2899)
  • Physiology (4351)
  • Plant Biology (9263)
  • Scientific Communication and Education (1587)
  • Synthetic Biology (2558)
  • Systems Biology (6787)
  • Zoology (1470)