Multistage carcinogenesis: population-based model for colon cancer

Area of Science:

• Oncology
• Genetics
• Mathematical Modeling

Background:

• Multiple mutations are implicated in colon cancer development.
• Previous models suggest a link between mutations and colon cancer incidence.

Purpose of the Study:

• To estimate the number of mutations required for colon carcinogenesis.
• To compare mathematical models with colon cancer incidence data from human populations.

Main Methods:

• Likelihood analysis was used to fit mathematical models to incidence data.
• Models included the Armitage-Doll model and two- and three-mutation models with cell proliferation kinetics.
• Data were analyzed from the general population of Birmingham, England, and patients with familial adenomatous polyposis (FAP).

Main Results:

• Models with two or three rate-limiting events equally described colon cancer incidence rates when cell kinetics were considered.
• The incidence rate in the general population versus FAP patients suggests FAP gene mutations are not rate-limiting.
• The three-mutation model aligns better with reported mutations and laboratory mutation rates than the two-mutation model.

Conclusions:

• The three-mutation model provides a better fit for colon cancer development.
• A mutation at the FAP locus may not be a rate-limiting step but could indirectly influence stem cell proliferation.
• Colon cancer development in FAP patients may not follow the retinoblastoma paradigm.