Dominant inheritance in human cancer.

Familial aggregations of defined malignancies are of great importance for determining the genetic factors involved, as has been demonstrated for familial and sporadic retinoblastoma. In nearly all organs, neoplasms occur that are inherited similar to familial retinoblastoma (Rb). For example, more than 5% of all women suffering from breast cancer belong to breast cancer families in which the occurrence of the malignancy suggests an autosomal dominant pattern of inheritance. Familial colon cancer is associated with several well-known autosomal dominantly inherited polyposis syndromes, and also other susceptibilities without obvious clinical features. Site-specific cancers are often accompanied by other malignancies. In addition, there seem to be predispositions to a wider range of different, but well-defined neoplasms: e.g., adenocarcinomatosis of the colon and the endometrium, or the Li-Fraumeni/SBLA syndrome. The latter shows a spectrum of sarcoma, brain tumours, breast cancer, leukaemias, lung and adenocortical cancer. The genes leading to these types of dominantly inherited predispositions appear to be the tentatively so-called tumour suppressor genes, for which the Rb gene serves as a model. It manifests itself recessively on the level of the individual cell, which means both alleles must be deleted or inactivated before a retinoblast develops into a neoplastic cell. Clinical, epidemiological and molecular genetic studies have yet to establish whether the Rb model can be extended to all other forms of dominantly inherited human cancers.