Studies on inherited cancers: outcomes and challenges of 25 years.

Research on the dominantly inherited cancer-susceptibility syndromes over the past 25 years has defined the genetic basis of most of these diseases, usually through linkage analysis on families carrying the disease, and identification and analysis of the genes responsible. At present, almost all of these genes have been cloned and, in most cases, the findings have lent full support to Knudson's original hypothesis: germline carriers of mutations in cancer susceptibility genes are predisposed to developing cancer, the resultant tumours contain aberrations in the remaining copy of that gene, and these genes often play a pivotal role in the genesis of the equivalent sporadic cancers, whereby two somatic events result in the disruption of both copies of the gene. This perspective highlight some of the issues that have been raised by these studies, and points to a few of the areas of future research that might help to resolve them.