| The retinoblastoma (Rb) gene
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Table 41-3.
Selected inherited cancer syndromes. |
| Body_ID: None |
| Selected inherited cancer syndromes |
| Body_ID: T041003.50 |
| Syndrome | Cancer | Gene product |
| Body_ID: T041003.100 |
| familial retinoblastoma | retinoblastoma | Rb 1: cell cycle and transcriptional regulation |
| Body_ID: T041003.150 |
| | osteosarcoma | |
| Body_ID: T041003.200 |
| Li-Fraumeni | sarcomas, adrenocortical carcinomas | p53: transcription factor |
| Body_ID: T041003.250 |
| | carcinomas of breast, lung, larynx, | DNA damage and stress |
| Body_ID: T041003.300 |
| | and colon | |
| Body_ID: T041003.350 |
| | brain tumors | |
| Body_ID: T041003.400 |
| | leukemia | |
| Body_ID: T041003.450 |
| Familial adenomatous polyposis (FAP) | colorectal cancer: colorectal adenomas, duodenal and gastric tumors,jaw osteomas, and desmoid tumors (Gardner syndrome),medulloblastoma (Turcot syndrome) | APC: regulation of β-catenin, microtubule binding |
| Body_ID: T041003.500 |
| Wiedmann-Beckwith syndrome | Wilm's tumor, organomegaly, hemihypertrophy, hepatoblastoma,adrenocortical cancer | p57/KIP2: cell cycle regulator |
| Body_ID: T041003.550 |
| neurofibromatosis type 1 (NF1) | neurofibrosarcoma AML brain tumors | GTP-ase activating protein (GAP) for p21Ras |
| Body_ID: T041003.600 |
| hereditary papillary renal cancer | renal cancer | Met |
| Body_ID: T041003.650 |
| | | HGF-receptor |
| Body_ID: T041003.700 |
| familial melanoma | melanoma | p16 (CDK): inhibitor of cyclin-dependent kinase (CDK4/6) |
| Body_ID: T041003.750 |
| | pancreatic cancer | |
| Body_ID: T041003.800 |
| | dysplastic nevi | |
| Body_ID: T041003.850 |
| | atypical moles | cyclin-dependent kinase (CDK4) |
| Body_ID: T041003.900 |
|
| Body_ID: T041003.950 |
AML, acute myelogenous leukemia; HGF, hepatocyte growth factor; KIP2, 57 KDa inhibitor of cyclin-CDK complexes.
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| page 596 |  | | page 597 |
| FAMILIAL ADENOMATOUS POLYPOSIS (FAP) AND COLON CANCER |
| Investigation of inherited cancer genes has advanced our understanding of somatic mutations in sporadic cancers and the function of these signaling elements in the normal regulation of cell growth. FAP, a rare condition affecting 1 in 7000 in the USA, is characterized by inactivating germline mutations in the APC gene. Although germline mutations in APC are infrequent, somatic mutations in APC are present in more than 70% of adenomatous polyps and carcinomas of the colon and rectum. APC acts to promote degradation of the protein, β-catenin, in normal cells; β-catenin, through its interactions with transcription factors, drives transcriptional activation. Thus, in APC-mutated cells, β-catenin accumulates and binds and activates transcription factors, resulting in deregulated growth control and cancer. Additional evidence for a key role for β-catenin signaling in cancer development has been provided by cancer cells bearing β-catenin mutations that render β-catenin insensitive to APC-mediated degradation and repression of transcriptional activation. |
Comment. Studies of the use of aspirin in humans have suggested that inhibitors of cyclo-oxygenase (COX: enzymes that have a key role in the conversion of the inflammatory mediator, arachidonic acid, to various prostaglandins; see Chapter 38) can alter the natural history of colon cancer. A randomized, double blind trial showed that aspirin prevented adenomas from arising in patients with previous colorectal cancer. Indeed, not only does the risk of the disease appear to be reduced in regular users of aspirin, but also the risk of fatal or metastatic colon cancer appears to be reduced by up to 50% in chronic users of the drug. This effect of aspirin appears to result from inhibition of COX-2, which is expressed at high levels in most colon tumors, and reflects the important roles that prostaglandins have in the pathogenesis of cancer as a result of their modulation of a wide range of cellular responses such as mitogenesis, cellular adhesion, immune surveillance, and apoptosis. |
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| The rare human cancer, retinoblastoma, affords a good example of a cancer syndrome that has been an important source of information on tumor suppressor genes. In this cancer, neural progenitor cells in the immature retina are transformed by an unusually low number of mutations. Retinoblastoma occurs in childhood, with an incidence of about 1 in 20000. In the hereditary form of the disease, multiple tumors occur, affecting both eyes, whereas in the (very rare) nonhereditary form, only one eye is affected by a single tumor. Sufferers of both forms of the disease were found to
have a deletion of a specific band on chromosome 13; analysis of this genetic defect in individual patients showed that patients with the hereditary disease had a deletion or loss-of-function mutation of the Rb gene in every cell. This mutation predisposed these cells to become cancerous, because a single somatic mutation to knock out the remaining copy of Rb gene was sufficient to initiate a cancer. In fact, in approximately 70% of cases, the second Rb gene and its flanking regions on the chromosome are either completely deleted, or replaced with the corresponding regions of the defective chromosome by a process of mitotic recombination (loss of heterozygosity). In contrast, although patients with the nonhereditary disease show no mutations in either copy of their Rb genes in noncancerous cells, both copies are defective in
their cancer cells. This explains the rarity of the nonhereditary disease, because somatic mutations in both copies of Rb in a single retinal cell are required for transformation. Given the key role of the retinoblastoma protein, Rb, in the negative regulation of cell cycle progression (see above), it is perhaps not surprising that loss of Rb function plays such a major part in tumor progression. Thus, although retinoblastoma is a rare disease, mutations of Rb are not, and occur in many of the most common cancers such as lung, breast, and bladder carcinomas.
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