RT Journal Article
SR Electronic
T1 A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.29.424555
DO 10.1101/2020.12.29.424555
A1 Saskia Haupt
A1 Nils Gleim
A1 Aysel Ahadova
A1 Hendrik Bläker
A1 Magnus von Knebel Doeberitz
A1 Matthias Kloor
A1 Vincent Heuveline
YR 2021
UL http://biorxiv.org/content/early/2021/07/06/2020.12.29.424555.abstract
AB 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 StatementThe authors have declared no competing interest.