TUMOR SUPPRESSOR GENES

     Tumor suppressor genes can be defined as genes which encode proteins that normally inhibit the formation of tumors. Their normal function is to inhibit cell proliferation, or act as the “brakes” for the cell cycle. Mutations in tumor suppressor genes contribute to the development of cancer by inactivating that inhibitory function. Mutations of this type are termed loss-of-function mutations. As long as the cell contains one functional copy of a given tumor suppressor gene (expressing enough protein to control cell proliferation), that gene can inhibit the formation of tumors. Inactivation of both copies of a tumor suppressor gene is required before their function can be eliminated. Therefore, mutations in tumor suppressor genes are recessive at the level of an individual cell. As we will see, the inactivation of tumor suppressor genes plays a major role in cancer.

A. Retinoblastoma
     Retinoblastoma (RB) is a rare childhood tumor of the eye (see clinical correlate). Most cases (60-70%) are sporadic (as opposed to inherited), occur unilaterally (affecting one eye), and present in children 1-4 years of age. The remaining 30-40% of patients have a hereditary form of retinoblastoma and thus have inherited a germline cancer predisposing mutation (see below). These children tend to acquire tumors earlier than those with sporadic disease and are more likely to have multiple tumors in one (unilateral) or both (bilateral) eyes. In families with the inherited form of retinoblastoma, the disease shows an autosomal dominant inheritance pattern.

B. Genes encoding
     Cdk inhibitors are tumor suppressor genesMutational inactivation of CDK inhibitors also drives the cell cycle by unregulated activation of cyclins and CDKs. One such inhibitor, encoded by the p16 gene, is a common target of deletion or mutational inactivation in human tumors. Recall that p16 is an inhibitor of Cdk4-cyclin D complexes. Germline mutations of p16 are associated with a subset of hereditary melanomas. Somatically acquired deletion or inactivation of p16 is seen in 75% of pancreatic cancers; 40-70% of glioblastomas; 50% of esophageal cancers; and 20% of non-small cell lung cancers, soft tissue sarcomas, and bladder cancers. The loss of p16 leads to increased Cdk4-cyclin D activity. This results in phosphorylation and inactivation of Rb, leading to activation of E2F and cyclin E transcription. In fact, in cells that harbor mutations in either p16, CDK4, or cyclin D, the function of RB1 is disrupted even if RB1 itself is not mutated.

C. p53
    a key tumor suppressorp53, located on chromosome 17p13.1, is the single most common target for genetic alteration in human tumors. In fact, more than 50% of human tumors contain mutations in this gene! Thus it is among the most important “brakes” on tumor formation. Homozygous loss of the p53 gene is found in virtually every type of cancer, including carcinomas of the breast, colon, and lung – the three leading causes of cancer deaths. In most cases, the inactivating mutations affecting both p53 alleles are acquired in somatic cells. In some cases, although it is rare, individuals inherit a mutant p53 allele. As with RB1, inheritance of one mutant allele predisposes these individuals to develop malignant tumors because only one additional “hit” is needed to inactivate the second, normal, allele. Inactivation of the second p53 allele leads to increased cell proliferation, decreased apoptosis, and tumor development. These individuals have a rare cancer predisposition syndrome called Li-Fraumeni syndrome, and have a 25-fold greater chance of developing a malignant tumor by age 50, compared with the general population. In contrast to patients who inherit a mutant RB1 allele, the spectrum of tumors that develop in patients with Li-Fraumeni syndrome is quite varied. The most common types of tumors.

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