Tumor Suppressor Genes

In 1971, while researchers were still identifying new members of the family of oncogenes, Alfred G. Knud-

TABLE 1.1. Oncogenes."

Growth factors or receptors for growth factors

PDGF: platelet-derived growth factor (brain and breast cancer)

erb-B receptor for epidermal growth factor (brain and breast cancer)

erb-B2 receptor for growth factor (breast, salivary, and ovarian cancers)

RET growth factor receptor (thyroid cancer)

Cytoplasmic relays in stimulatory signaling

Kras activated by active growth factor receptor proteins (lung, ovarian, colon,

pathways

and pancreatic cancer)

N-ras activated by active growth factor receptor proteins (leukemias)

c-src, a protein kinase that becomes overactive in phosphorylation of target proteins

Transcription factors that activate growth

c-myc activates transcription of growth stimulation genes (leukemia, breast,

promoting genes

stomach, and lung cancer)

N-myc (nerve and brain cancer)

L-myc (lung cancer)

c-jun and c-fos function as transcription factors

Molecules of other types

Bcl-2 normal protein blocks cell suicide (lymphoma)

Bcl-1 codes for cyclin D1, stimulatory protein of the cell cycle (breast, neck, and

head cancers)

MDM2 codes for antagonist of p53 (sarcomas)

These genes are associated with the stimulation of cell division. Cancers result from mutation in only one allele of the gene.

These genes are associated with the stimulation of cell division. Cancers result from mutation in only one allele of the gene.

Inactivation Tumor Suppressor Genes

FIGURE 1.1. The relationship between the activation of oncogenes or the inactivation of tumor suppressor genes (TSGs) and the cell cycle. When the normal activity of these cancer genes is lost, cells are pushed toward the S phase of the cell cycle, inevitably leading to increased mitotic activity and uncontrolled proliferation.

FIGURE 1.1. The relationship between the activation of oncogenes or the inactivation of tumor suppressor genes (TSGs) and the cell cycle. When the normal activity of these cancer genes is lost, cells are pushed toward the S phase of the cell cycle, inevitably leading to increased mitotic activity and uncontrolled proliferation.

son,22 by studying several cases of retinoblastoma (Rb) demonstrated that this rare eye tumor affecting infants and young children, is likely to depend on two sequential mutations affecting a key gene, still unknown at that time. The hypothesis, formulated by Knudson to explain the different clinical phenotypes of retinoblastoma, was based on the study of the relationships between age at diagnosis, clinical pheno-type (unilateral vs bilateral disease), and number of tumor foci per affected eye. When the first mutation is transmitted genetically from one of the parents, all the somatic cells of the individual will carry it. As a consequence, the individual will be likely to develop, at an early age, a tumor affecting both eyes (bilateral Rb), with multiple foci and, given the first mutation in all somatic cells, an increased susceptibility to develop second nonocular tumors. On the other hand, when both the first and second mutations affect the somatic cell (the retinoblast), the individual will develop, later in life, a retinoblastoma affecting, commonly a single eye (unilateral Rb), with a single tumor focus and no susceptibility to second nonocular tumors.

Molecular studies using genetic markers that are heterozygous in the majority of individuals showed that tumor genotypes of affected patients usually differ from the corresponding constitutional genotype (e.g., the genetic makeup of patient's blood cells). In its most simplified expression, this was evidenced as difference in the electrophoretic migration pattern of selected DNA markers. When these markers were found to show a typical two-band model indicating heterozygosity in the patient's constitutional genotype (e.g., nucleated blood cells), it was common to find a single band, indicating homozygosity, when the tumor DNA of the same patient was comparatively analyzed (Figure 1.2). As described by Cavenee et al.,23 this phenomenon, called loss of heterozygosity (LOH), was considered to be specific to tumors involving the loss or inactivation of a new type of cancer gene and, as shown in Figure 1.2, seemed to represent the physical demonstration of the "two-hit" model hypothesized by Knudson in the genesis of retinoblastoma.

With the introduction of the polymerase chain reaction (PCR), which allows the amplification of large amounts of specific DNA fragments, and the concurrent discovery of a number of new genetic markers from within specific genes, molecular analysis of cancer became available on a larger scale and armed clinical oncologists with a powerful new tool for genetic counseling and prenatal/presymptomatic diagnosis of different types of cancer.24 Further investigations of a suspect gene for the development of this tumor led to the identification of the gene Rb1, located in the long arm of chromosome 13 (13q14), and, most important, opened a completely new line of research on cancer genes. When

FIGURE 1.2. Schematic illustration of the "two-hit" hypothesis of cancer development. A number of different mechanisms have been postulated to explain how a heterozygous genetic marker is reduced to homozygosity in the tumor cells. Whatever the mechanism involved, the final result is a characteristic band pattern when DNA electrophoresis is performed to compare the constitutional (blood) and the tumor genotypes. The tumor cells are said to show a loss of heterozygosity (LOH). The bonds for the three retinoblas-tomas at the bottom of the figure show a clear LoH pattern.

considered from the point of view of Mendelian genetics, Rb1, as opposed to the known oncogenes, seemed to behave in a "recessive" way. That is, to develop a fully expressed disease, it seemed necessary for both copies of the gene to be lost or inactivated, thus implying that even a single functional gene is normally sufficient to inhibit the proliferative activity of the cell.25 Therefore, it became evident that the cell contains genes of two different types that regulate its proliferative capacity, one with stimulatory (oncogenes) and the other with inhibitory activity. This last category of cancer genes, of which Rb1 represents the prototype,26,27 was called tumor suppressor genes (TSGs).

TSGs normally function to inhibit, or "put the brakes on," the cycle of cell growth and division; that is, they function to prevent the development of tumors. As for oncogenes, this task is accomplished by a number of heterogeneous proteins in a number of different ways.

• TGF-jS can stop the growth of normal cells of various kinds; some colon cancer cells become obliv ious to TGF-jS by inactivating a gene that encodes a surface receptor for this substance.

• A variety of cancers discard the p15 gene, which normally codes for a protein needed to shut down the machinery guiding the cell through its growth cycle.

• Some TSGs, such as NF1, the gene for neurofibro-matosis type 1, block the flow of signals through the growth stimulatory pathway (RAS oncogene).

• Some other genes, currently considered TSGs, are involved in the repair of DNA mismatches; still others are involved in the apoptotic cascade.

More recently, a simplified classification proposed two different functions for these genes, namely that of caretakers, or guardians of the integrity of the genetic material, and that of gatekeepers, or regulators of tumor growth by inhibition of cell growth or by promotion of cell death. According to this classification, both caretakers and gatekeepers share the characteristics of "recessive" genes (i.e., two mutations are necessary for inactivation), whose mutation predisposes to neoplasia. However, the caretaker pathway to neoplasia, leading to genetic instability, requires more mutational events than the gatekeeper pathway.28 A short list of TSGs is given in Table 1.2.

The discovery of TSGs seemed to complete the picture of how the cell can be transformed by endogenous influences of opposite sign on its proliferative activity, that is, the activation of the stimulatory pathway (oncogenes) or the disruption of the inhibitory pathway (TSGs). In both cases, the deregulation implies the loss of the normal control these genes exert on the entrance into the cell cycle or the permanence of the cell in a quiescent state (G0) (Figure 1.1).

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