EXCESS OF MULTIFOCAL TUMORS IN NEPHROBLASTOMA - IMPLICATIONS FOR MECHANISMS OF TUMOR-DEVELOPMENT AND GENETIC-COUNSELING

Referring to the mutational theory of carcinogenesis in embryonal tumo rs, it is commonly accepted that patients with multifocal tumors are h ereditary cases. This is based on the implicit assumption that each tu mor results from a single mutational event occurring in a cell that ha s already inherited a mutation, and that these tumors are independent. We studied the distribution of tumors in 1,868 cases where the focali ty was known (SIOP 1, 2, 5 and 6). Using all the supposed gene carrier s (bilateral and unilateral multifocal cases), and assuming a Poisson distribution of tumors, we estimated the mean number m of tumors in ea ch kidney to be 0.37. Comparing the observed distribution of cases to the expected one, we found a very bad fit to this hypothesis (P < 10(- 9)). This is due to an excess of multifocal tumors, particularly in un ilateral cases. These findings have important implications in genetic counseling, since the usual practice of considering multifocal tumor p atients as hereditary cases may result in a large overestimate of the recurrence risk in such cases. The implications for the mechanisms of tumor development are also discussed.