AbstractIntroductionLynch 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.MethodsWe suggest 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.ResultsAs 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.ConclusionThe 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 for effective surveillance protocols for LS carriers.Graphical AbstractOverview of the computational model of colonic crypts.Top: The colonic crypt is represented by a cylinder consisting of stem cells (red) at the bottom, transit-amplifying cells (orange) in the middle and fully-differentiated (FD) cells (green) at the top of the crypt. An active stem cell populates the crypt at any point in time. As we model LS, all cells are initialized with a single mutation in exactly one of the MMR genes. The cylinder is transformed into a rectangle with periodic boundary conditions, where the cells are represented by a Voronoi tessellation. Bottom: For each cell type, we model the cell cycle including cell division, possible mutations in one of the MMR genes, in APC and CTNNB1, and multiple death mechanisms.
Computational model investigates the evolution of colonic crypts during Lynch syndrome carcinogenesis
