Prince Takamatsu memorial lecture. Rare cancers: clues to genetic mechanisms.

Virtually every kind of cancer can occur in hereditary form. Such hereditary cancers are rare, but have been informative out of proportion to their frequencies because some of them have illuminated mechanisms important in the genesis of cancer generally. The prototypes of hereditary cancer have been two uncommon tumors, retinoblastoma and Wilms' tumor. Genetic epidemiologic analysis of these tumors led to the formulation of a model for their origin following two events. According to this model the first event could already be present in the germline, thereby giving rise to the heritable forms of these diseases; the second event would occur somatically in one or more cells of the relevant organ. Both events would occur somatically in the non-hereditary form. It was proposed that the two events involved mutation or loss of both copies of a particular gene; i.e., these genes are recessive in oncogenesis. Cytogenetic analyses of rare deletion cases of retinoblastoma permitted the localization of the retinoblastoma gene to chromosomal band 13q14. Deletion was also proposed as the mechanism for the rare conjunction of Wilms' tumor and aniridia; deletions of chromosomal band 11p13 were subsequently found. Deletions were also found in tumor cells of some patients with the non-hereditary forms of these two tumors, lending support to the idea that the same loci were involved in the two forms. The application of molecular genetic techniques led to verification of the recessive hypothesis for both retinoblastoma and Wilms' tumor and to the cloning of the gene of the former. These accomplishments are leading to a new understanding of mechanisms of oncogenesis and their involvement even in the common cancers of adults.