Multi-step Tumorigenesis and Genome Instability

Abstract

The characterization of the growth of primary and metastatic tumors is crucial for the diagnosis and therapy of cancer. The process of tumorigenesis comprises multiple steps of mutations in cancer driver genes that provide the cell clone with a selective growth advantage over its neighboring cells. Importantly, the individual nature of each cancer case is based on two to six driver mutations out of a choice of some 500 oncogenes and tumor suppressor genes as well as on a flexible order how the hallmarks of cancer are obtained. The extraordinary ability of the different DNA repair pathways to maintain tens of thousands of DNA lesions, which each cell of our body is daily exposed to, is the reason that only approximately 40 mutations accumulate per cell and year. The vast amount of these mutations are passengers and only a few are drivers. The lifetime risk of many types of cancers correlates well with the number of stem cell divisions used for maintenance of tissue homeostasis. Accordingly, only a third of the cancer risk would be based on environmental exposure and inherited predisposition, while the majority has a stochastic basis.