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Figure 2-1. Observed (squares) and predicted (lines) incidence of colorectal cancer by race and gender in the Surveillance, Epidemiology, and End Results (SEER) registry (1984). (From Luebeck and Moolgavkar,1 with permission.)

of these hits are thought to be mutational in origin and to result from chromosomal damage or base changes in DNA. The number of hits needed to produce the initiation of a malignant event may vary from one to six or more. However, progression to a full-blown invasive metastatic cancer almost always requires multiple hits. A few examples will make the point.

In chronic myleogenous leukemia (CML), there is an inciting chromosomal translocation that involves a piece of chromosome 22 being lost. This was first observed by Nowell and Hungerford,2 who named this small chromosome the Philadelphia chromosome. It was later shown by Rowley3 that this was a reciprocal translocation between chromosomes 9 and 22 (Fig. 2-2), which produces a chimeric protein called Bcr/Abl that is a constitutively active tyro sine kinase promoting cell proliferation (see Chapter 4). Thus, CML appears to be triggered by this one-hit event and is probably the reason why the drug Gleevec, which targets this kinase, is effective as a single agent in CML.

A second example is retinoblastoma. There are two forms of this disease, hereditary and spontaneous. Both forms appear to require two initiating genetic events, leading Knudson, who studied this disease in detail, to postulate the two-hit hypothesis.4 In the hereditary form, one genetic mutation is inherited at birth and a second one occurs later (Fig. 2-3). This must be the case, since every cell in the eye contains the hereditary mutation, but only three to four tumors on average develop in a retinal cell population of several million cells in affected individuals.

Figure 2-2. A comparison of karyotypes. a. Chronic myelogenous leukemia, showing the typical 9;22 translocation and an otherwise normal karyotype. b. Non-small cell carcinoma of the lung, showing abnormalities of both number and structure. The arrows indicate aberrant chromosomes. (From Knudson,4 reprinted by permission from Macmillan Publishers Ltd.)

Figure 2-2. A comparison of karyotypes. a. Chronic myelogenous leukemia, showing the typical 9;22 translocation and an otherwise normal karyotype. b. Non-small cell carcinoma of the lung, showing abnormalities of both number and structure. The arrows indicate aberrant chromosomes. (From Knudson,4 reprinted by permission from Macmillan Publishers Ltd.)

Most adult solid cancers (e.g., colon, lung, breast, prostate) likely require several hits to achieve a full malignant state. The best example of this is colon cancer, for which at least five hits appear to be required to produce an invasive carcinoma (Fig. 2-4). Because of genetic instability, a characteristic of most solid cancers, many more genetic alterations are frequently seen in later stages of cancer progression.5 This has been ascribed to a ''mutator phenotype'' observed in many cancers.6 In contrast to single genetic defect cancers such as CML, the prospect of finding effective single therapeutic agents is unlikely for most solid tumors. Most likely, multiple aberrant cell signaling pathways will need to be inhibited for effective chemotherapeutic regimens to be achieved. However, if there are identifiable time intervals between the multiple hits that lead to cancer, perhaps detectable by early screening for surrogate markers of progression, there may be a window of opportunity for preventive agents (see Chapter 9).

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