Multistage carcinogenesis and the incidence of colorectal cancer

Abstract

We use general multistage models to fit the age-specific incidence of colorectal cancers in the Surveillance, Epidemiology, and End Results registry, which covers approximately 10% of the U.S. population, while simultaneously adjusting for birth cohort and calendar year effects. The incidence of colorectal cancers in the Surveillance, Epidemiology, and End Results registry is most consistent with a model positing two rare events followed by a high-frequency event in the conversion of a normal stem cell into an initiated cell that expands clonally to give rise to an adenomatous polyp. Only one more rare event appears to be necessary for malignant transformation. The two rare events involved in initiation are interpreted to represent the homozygous loss of adenomatous polyposis coli gene function. The subsequent transition of a preinitiated stem cell into an initiated cell capable of clonal expansion via symmetric division is predicted to occur with a frequency too high for a mutational event but may reflect a positional effect in colonic crypts. Our results suggest it is not necessary to invoke genomic instability to explain colorectal cancer incidence rates in human populations. Temporal trends in the incidence of colon cancer appear to be dominated by calendar year effects. The model also predicts that interventions, such as administration of nonsteroidal anti-inflammatory drugs, designed to decrease the growth rate of adenomatous polyps, are very efficient at lowering colon cancer risk substantially, even when begun later in life. By contrast, interventions that decrease the rate of mutations at the adenomatous polyposis coli locus are much less effective in reducing the risk of colon cancer.

Fig 1.

Schematic representation of the TSCE model (A) for colon cancer together with its three- (B), four- (C), and five-stage (D) extensions. Shown is the stepwise progression of a normal stem cell to an initiated cell. With the exception of the TSCE model, this involves preinitiation stages. Once initiated, stem cells may divide symmetrically with cell division rate α, die or differentiate with rate β, or undergo an asymmetric division with rate μ_{k − 1} that results in a malignant cell.

Fig 2.

Observed (squares) and predicted (lines) incidence of colorectal cancer by race and gender in the SEER registry (1984). Predicted incidence is for the four-stage model using the parameter estimates in Table 1.

Fig 3.

Observed and predicted (using the four-stage model) incidence of colorectal cancer in SEER (1973–1996) by gender for the white population. Shown as a function of birth year (A and B) and as a function of calendar year (C and D) for the age groups 55–59 through 80–84. Similar results are obtained for the African American population.

Fig 4.

The formation of an adenoma in the four-stage model, schematically. The basic steps involved (left to right) in a section of the colonic crypt: normal stem cell division maintaining the crypt. Step 1: rare mutation in a stem cell inactivates one allele of the APC gene. Unless the normal (APC–wild-type) stem is inactivated or dies, the crypt may become mosaic, i.e., may consist of a mixture of APC–wild-type and APC+/− cells. Step 2: second rare event leads to biallelic inactivation of the APC gene in a stem cell. Step 3: frequent asymmetric divisions of the defective stem cell populate proliferative zone with APC−/− progeny that may undergo clonal expansion.

Fig 5.

Expected age-specific incidence of colorectal cancer assuming that an intervention occurs at ages 20, 40, or 60, or not at all. (Left) Hypothetical intervention that reduces the net cell proliferation rate of cells in polyps by 50%. (Right) Hypothetical intervention that reduces the rate of APC mutations by 50%.