Age-specific incidence data indicate four mutations are required for human testicular cancers

Abstract

Normal human cells require a series of genetic alterations to undergo malignant transformation. Direct sequencing of human tumors has identified hundreds of mutations in tumors, but many of these are thought to be unnecessary and a result of, rather than a cause of, the tumor. The exact number of mutations to transform a normal human cell into a tumor cell is unknown. Here I show that male gonadal germ cell tumors, the most common form of testicular cancers, occur after four mutations. I infer this by constructing a mathematical model based upon the multi-hit hypothesis and comparing it to the age-specific incidence data. This result is consistent with the multi-hit hypothesis, and implies that these cancers are genetically or epigenetically predetermined at birth or an early age.

Figure 1. This is a comparison between the observed (SEER-17, 2000–2007) age-specific incidence for testicular cancers and that predicted by the multi-hit model with four mutations.

The black circles represent the measured incidence, the error bars are 95% confidence intervals, and the green solid line represents the incidence predicted by the multi-hit model with four mutations.

Figure 2. This figure compares the best fit models for three, four, and five mutations.

To emphasize the differences, only regions before the age of 25 and after the age of 50 are shown. All three models show close fit to the data between 25 and 50 years of age. The models with four mutations and five mutations are identical after the age of 50.