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

2021 ◽  
Vol 1 (2) ◽  
Author(s):  
Saskia Haupt ◽  
Nils Gleim ◽  
Aysel Ahadova ◽  
Hendrik Bläker ◽  
Magnus Knebel Doeberitz ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Computational Model ◽  
Colonic Crypts

scholarly journals Computational model investigates the evolution of colonic crypts during Lynch syndrome carcinogenesis

2020 ◽  
Author(s):  
Saskia Haupt ◽  
Nils Gleim ◽  
Aysel Ahadova ◽  
Hendrik Bläker ◽  
Magnus von Knebel Doeberitz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Lynch Syndrome ◽  
Computational Model ◽  
Voronoi Tessellation ◽  
Single Mutation ◽  
Cell Dynamics ◽  
Mmr Genes ◽  
Colonic Crypts ◽  
Mmr Deficiency ◽  
Mutational Processes

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.

scholarly journals DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome

2018 ◽  
Vol 31 (10) ◽  
pp. 1608-1618 ◽  
Author(s):  
Rish K. Pai ◽  
Beth Dudley ◽  
Eve Karloski ◽  
Randall E. Brand ◽  
Neil O’Callaghan ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Dna Mismatch ◽  
Colonic Crypts ◽  
Repair Protein ◽  
Mismatch Repair Protein

Aldosterone-induced non-genomic inhibition of intermediate conductance K+ channels in human colonic crypts is mediated by protein kinasse C

2001 ◽  
Vol 120 (5) ◽  
pp. A528-A528
Author(s):  
K BOWLEY ◽  
G SANDLE
Keyword(s):  
K Channels ◽  
Colonic Crypts

cAMP-mediated activation of NBC (Na+/HCO2− cotransporter) and NKCC (Na+/K+/2Cl− cotransperter) in murine colonic crypts

2001 ◽  
Vol 120 (5) ◽  
pp. A698-A698
Author(s):  
O BACHMANN ◽  
K WUECHNER ◽  
H ROSSMANN ◽  
J LEIPZIGER ◽  
M GREGOR ◽  
...  
Keyword(s):  
Colonic Crypts

Molecular Screening for the Lynch Syndrome—Better Than Family History?

2007 ◽  
Vol 2007 ◽  
pp. 253-254
Author(s):  
P.J. Loehrer
Keyword(s):  
Family History ◽  
Lynch Syndrome ◽  
Molecular Screening ◽  
Better Than

Predicting Lynch Syndrome Propensity to Cancer

2006 ◽  
Vol 39 (21) ◽  
pp. 52
Author(s):  
MARY ANN MOON
Keyword(s):  
Lynch Syndrome

Attentive Tracking in the Perception of Animacy: A Computational Model of "Chasing" vs. "Stalking"

2013 ◽  
Author(s):  
Tao Gao ◽  
Chris L. Baker ◽  
Joshua B. Tenenbaum
Keyword(s):  
Computational Model

Inference making and memory for text: A computational model

2001 ◽  
Author(s):  
Paul Van Den Broek ◽  
Yuhtsuen Tzeng ◽  
Sandy Virtue ◽  
Tracy Linderholm ◽  
Michael E. Young
Keyword(s):  
Computational Model ◽  
Inference Making ◽  
Memory For Text

Computational Model of Novel Popout

1992 ◽  
Author(s):  
William A. Johnston ◽  
Kevin J. Hawley ◽  
James M. Farnham
Keyword(s):  
Computational Model

DIAGNOSE AND DISREGARD POLICY CAN BE IMPLEMENTED IN PATIENTS WITH LYNCH SYNDROME WHEN DONE BY EXPERT COLONOSCOPISTS

2019 ◽  
Author(s):  
A Gavrić ◽  
L Rivero Sanchez ◽  
C Arnau ◽  
J Herrero ◽  
D Remedios ◽  
...  
Keyword(s):  
Lynch Syndrome
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