Genetic predisposition and somatic diversification in tumor development and progression.

Studies on human cancer predisposition syndromes have contributed significantly to our understanding on tumor initiation and progression. Work performed on hereditary colon cancer has been particularly fruitful. Much of the molecular background of the various intestinal polyposis syndromes, such as familial adenomatous polyposis (FAP), juvenile polyposis, and Peutz-Jeghers syndrome, has been revealed, pinpointing several key cancer-associated genes. Studies on hereditary nonpolyposis colorectal cancer (HNPCC) have revealed a novel mechanism of tumorigenesis; genomic instability caused by defective DNA mismatch repair (MMR). Understanding the molecular background of these diseases helps us to understand tumor initiation in the affected individuals. Relatively little is known about the details of tumor progression in hereditary and sporadic neoplasia. Certain additional gene mutations can be associated with advancing stages of the disease, but the pace and tempo of the process have remained obscure. A high mutation rate in MMR-deficient tumors has provided a new approach in the analysis of human tumor dynamics. Microsatellite (MS) sequences are frequently mutated in MMR deficient tumors. The high mutation rate allows the use of microsatellite mutations as a tool for analyzing the past patterns of tumor progression. This approach is similar to the use of MS mutations in studying human evolution and migrations. Such tumor studies have revealed progression pathways that differ from the classic adenoma-cancer sequence. The reasons why and how molecular clocks may reveal something new about a well-studied problem are discussed.