Age-specific incidence of cancer: Phases, transitions, and biological implications

The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-10, Vol.105 (42), p.16284-16289
Main Authors: Meza, Rafael, Jeon, Jihyoun, Moolgavkar, Suresh H, Luebeck, E. Georg
Format: Article
Language:English
Subjects:
Age Distribution
Biological Sciences
Biology
Cancer
Carcinogenesis
Carcinogens
Colorectal cancer
Female
Genes
Genetic mutation
Humans
Lesions
Male
Modeling
Neoplasms - epidemiology
Neoplasms - pathology
Pancreatic cancer
Prophets
Secular variations
Sex Characteristics
Stem cells
Time Factors
Tumors
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Summary:The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the Surveillance Epidemiology and End Results (SEER) registry we show that the log-log model provides a poor description of the data, and that a much better description is provided by a multistage model that predicts two basic phases in the age-specific incidence curves, a first exponential phase until the age of [almost equal to]60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early-exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, whereas the linear phase reflects events leading to initiated cells that give rise to premalignant lesions because of abrogated growth/differentiation control. This model is consistent with Knudson's idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which is the result of recessive inactivation of a gatekeeper gene, such as the APC gene in the colon and the CDKN2A gene in the pancreas.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0801151105