Loss of tumor-suppressor gene function in cancer.

a,b, The classical Knudson two-hit model involves an initial mutational event (vertical arrowhead) that leads to gene inactivation during tumor development. Blue shaded bars indicate inactivated genes. LOH by non-disjunction, mitotic recombination or deletion results in the functional inactivation of both alleles. If the first mutation is inherited through the germ line, individuals carrying this mutation are often highly predisposed to tumor development. c, The mutational event can be followed by gene silencing through promoter methylation (vertical bars) without LOH. d, Biallelic silencing of both gene copies without LOH or gene mutation. e,f, Haploinsufficient tumor-suppressor genes do not need to lose both functional copies to confer increased risk. Loss of a single gene copy may occur by mutation, deletion or silencing, and the other functional allele may be retained. In some examples (f), a partially or completely nonfunctional allele may be inherited through the germ line, predisposing an individual to tumor development without requiring LOH or complete functional inactivation. Some 'low-penetrance' tumor susceptibility genes may be in this category.