Cancer Tutorial

Problem 7: Gatekeeper and Caretaker Genes

A "gatekeeper" gene specifies a protein product that is a specific regulator of the cell cycle. The Rb gene product is an example of a gatekeeper gene, and individuals inheriting a defect in one allele have a >1000 fold increased incidence of retinoblastoma. Another class of inherited gene defects is called a "caretaker" gene that determines stability of the genome. An individual with a mutation in a caretaker gene has around a 5-50 fold increased risk of cancer (Nature 386, 762 (97). The BRCA 1 and 2 genes associated with breast cancer are now postulated to be "caretaker" genes. The best explanation for why there is a wide difference in susceptibility for cancer between caretaker and gatekeeper genes:

	The gatekeeper genes are all proto-oncogenes, with mutations leading to the formation of oncogenes that directly regulate the cell cycle and cause the cell to grow as a cancer.
	Loss of both normal alleles of gatekeeper genes produces cancer. Loss of both normal alleles of caretaker genes still requires further mutations in gatekeeper genes for cancer to develop. Thus, the increased incidence of cancer is reduced.