The importance of suppressor genes became evident from the work of Knudson (1971) with retinoblastoma. A familial form of retinoblastoma occurs at a high rate and a sporadic form at a very low rate. Knudson argued that in the familial form 1 mutant allele with lost function is inherited from the affected parent. A somatic event during embryogenesis inactivates the normal allele inherited from the unaffected parent. Almost all the children of such pairs of parents exhibit bilateral retinoblastoma. In sporadic retinoblastoma, 2 somatic mutations are necessary, the second in a descendant of a cell that suffered the first. Those double events are much less likely than a single event, so the incidence of the sporadic form of retinoblastoma is much lower. Knudson elaborated the "2-hit hypothesis" in the early 1970s (Knudson 1971). By the middle 1970s, the location of the relevant gene was identified on chromosome 13 (Cavanee and others 1985); in the 1980s, the Rb gene was cloned and sequenced (Lee and others 1987). The Rb gene is present in all cases of retinoblastoma and associated sarcomas; it is sometimes present in cases of other tumors, such as small-cell lung-cancer, bladder cancer, and mammary cancer.

The action of radiation is a potential mechanism for deleting a suppressor gene. Alpha particles are particularly efficient at producing large deletions (for example, Metting and others 1992). Two radiation-induced breaks in the same arm of a chromosome can readily result in a deletion. Studies with defined restriction cuts in cellular and plasmid DNA have indicated that small deletions can also result from processing of single sites of DNA damage (Thacker 1994).

A suppressor gene acts recessively, so the deletion would have to occur in both chromosomes of a pair; this would be a very low-frequency event. In practice, the loss of the pair of suppressor genes often occurs by the process of somatic homozygosity (Cavanee 1989). One chromosome of a pair is lost, a deletion occurs in the other chromosome, and then the second chromosome and the deletion are replicated. Consequently, the cells in the tumor have 2 chromosomes that originated from the same parent. That has been shown to be a mechanism in retinoblastoma, small-cell lung-cancer, and glioblastoma; the case of glioblastoma is particularly interesting, inasmuch as somatic homozygosity must occur in 2 different chromosomes for this high-grade tumor to be produced (Cavanee 1989).

The list of suppressor genes whose location and function are known is growing steadily. The 2 most common and most intensively studied are the Rb gene and the p53 gene, both of which are directly involved in cell-cycle checkpoint control (Kasten and others 1991; Smith and others 1994).

GENOMIC INSTABILITY

The multistage nature of cancer is one of the most pervasive hypotheses in cancer research. The idea is over 60 years old and continues to derive support from research findings, such as recently from the work of Vogelstein and col-



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