Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium

Abstract

SummaryWe investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred.

Evolutionary Stem Cell Poker and Cancer Risks: the Paradox of the Large and Small Intestines

“…Measuring the numbers of stem cells per crypt is difficult because the experimental fate marker approaches used in mice (8) are impractical. However, other approaches that measure somatic alterations indicate that human crypts also contain multiple stem cells (12,16–20). A recent study indicated that certain selective mutations can increase colon crypt fission (from one to two crypts) above a baseline rate of ~0.7% per year, which can further favor progression (20).…”

“…However, other approaches that measure somatic alterations indicate that human crypts also contain multiple stem cells (12,16–20). A recent study indicated that certain selective mutations can increase colon crypt fission (from one to two crypts) above a baseline rate of ~0.7% per year, which can further favor progression (20). Very few studies have compared human SI and colon crypts, and a study with passenger methylation indicated that human SI and colon crypts contain multiple mitotic stem cells that divide at similar rates (21).…”

Cooperation of partially-transformed clones: an invisible force behind the early stages of carcinogenesis

“…In the case of a fast self-renewing tissue like the intestinal epithelium within which the cell-of-origin for common tumours is likely to be a stem cell 23 , the highly compartmentalized stem-cell niche might pose an effective barrier to oncogenic field effects. The intestinal epithelium is one of the most proliferative tissues subject to a high mutagenic burden and it has been broadly studied both mathematically 24,25 and experimentally 23,26,27 . A small group of adult stem cells reside within the colonic crypt and maintain the homeostasis of the villi lining the intestine 23 .…”

“…The intestinal epithelium is one of the most proliferative tissues subject to a high mutagenic burden and it has been broadly studied both mathematically 24,25 and experimentally 23,26,27 . A small group of adult stem cells reside within the colonic crypt and maintain the homeostasis of the villi lining the intestine 23 . Within the crypt and the villus, the balance between proliferation and differentiation is maintained by a complex network of signals (e.g., WNT, NOTCH, BMP, and EGF) generated by specialized Paneth cells within the crypt and cells within mesenchyme lining the crypt 27 .…”

“…Mutations in the WNT (e.g., APC or CTNNB), EGFR (e.g., KRAS, PIK3C or BRAF) and TGF-β (e.g., SMAD4) signalling pathways gradually render cells independent from niche signals to grow autonomously and promoting cancer. While it is still more likely that two mutations are acquired within adjacent stem cells rather than within one cell, neutral genetic drift or selection fix or purge genetic mutations within the crypt that will be thus, most of the times, monoclonal 23 . However, not all mutations occurs in the stem cells within the crypt 28 and tissue homeostasis is maintained by crypt fusion and fission leading to field cancerization and the possibility that partially-or non-transformed clones might interacts not within a monoclonal crypt but between patches harbouring different mutations 23,29 .…”