Genetic epidemiology of multistage carcinogenesis

It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.