Pretumor progression: clonal evolution of human stem cell populations.

Area of Science:

• Oncology
• Genetics
• Cell Biology

Background:

• Multistep carcinogenesis is typically viewed as tumor progression via clonal evolution.
• However, genetic alterations (mutations) can occur without visible phenotypic changes, suggesting genetic progression may precede tumor formation.

Purpose of the Study:

• To investigate the concept of "pretumor progression" where mutations accumulate in normal-appearing tissues.
• To develop a quantitative model for understanding early cancer development in colon crypt stem cells.

Main Methods:

• A quantitative model was developed to simulate mutation accumulation in colon crypt niche stem cells.
• The model considers random stem cell loss, niche succession, and mutation acquisition (drift or selection).
• Mutation rates were estimated to match colorectal cancer epidemiology.

Main Results:

• The model suggests most oncogenic mutations can accumulate in normal-appearing colon crypt stem cells.
• Crypt clonal evolution (niche succession) can occur without selection or visible phenotypic changes.
• It is theoretically possible for all cancer mutations to accumulate before visible tumor progression.

Conclusions:

• Pretumor progression, driven by mutations in normal stem cells, is a feasible mechanism for early cancer development.
• Visible tumor progression may not be necessary for the initial accumulation of cancer-driving mutations.
• This challenges the necessity of elevated mutation rates or tumorigenesis for early progression.