Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk
Fig 4
Gene correction reduces spread of TP53 mutations through FA tissue.
(A) Model of four cellular genotypes at two loci: FA cells (FANC–/TP53+) in grey; FA cells with TP53 mutations (FANC–/TP53–) in magenta; gene-corrected cells (FANC+/TP53+) in green; gene-corrected cells with TP53 mutations (FANC+/TP53–) in cyan. Arrows indicate transitions that can occur via mutation or gene correction. (B) Genotype-specific persistence coefficients for (A). (C-H) TP53– tissue coverage as a function of gene correction at 46 years in 0.33 mm2 simulated tissue sections, comparing no correction (Ø) to correction with or
. Panels used 100 simulations at a given persistence coefficient except in panels C,F where 300 simulations were performed. C-E show the proportion of tissue coverage at 46 years with (C) comparable TP53 mutation rates and persistence coefficients regardless of FA genotype, (D) an elevated TP53 mutation rate in FANC– cells (
,
) and equivalent TP53 persistence coefficients or (E) equal TP53 mutation rates in FANC– and FANC+ cells with elevated TP53 persistence coefficients in FANC– cells (
). Error bars represent standard errors. Yellow bars represent TP53 tissue coverage range from Martincorena et al. [48] for normal esophagus. (F-H): six representative tissue sections at 46 years from C-E, with colors corresponding to genotypes shown in (A). (G) Consequence of an 8-fold increase in
, and (H) a 4-fold increase in
.