Genes Involved in Oncogenesis

Two major classes of genes have been implicated in the development of cancer: oncogenes and tumor suppressor genes. Proto-oncogenes are cellular genes that are important for normal cellular function and code for various proteins, including transcriptional factors, growth factors, and growth factor receptors. These proteins are vital components in the network of signal transduction that regulate cell growth, division, and differentiation. Proto-oncogenes can be altered to form oncogenes, genes that, when translated, can result in the malignant transformation of a cell.

Oncogenes can be divided in 5 different classes based on their mechanisms of action. Changes in any of these normal cellular components can result in unchecked cell growth. Some oncogenes code for growth factors that bind to a receptor and stimulate the production of a protein. Other oncogenes code for growth factor receptors. These are proteins on the cell surface. When growth factors bind to a growth factor receptor, they can turn the receptor on or off. Mutational or post-translational modifications of the receptor can result in a receptor being permanently turned on with consequent unregulated growth. Signal transducers make up another class. Signal transducers are responsible for taking the signal from the cell surface receptor to the cell nucleus. NRAS, as described later, is an example of this class of protein. Transcription factors are molecules that bind to specific areas of the DNA and control transcription. MYC, described later, is an example of a transcription factor that results in overstimulation of cell division. The final class of oncogenes interferes with apoptosis. Cells that no longer respond to the signal to die can continue to proliferate.

The three main mechanisms by which proto-oncogenes can be activated include amplification, point mutations, and translocation (Table 486-1). MYC, which codes for a protein that regulates transcription, is an example of a proto-oncogene that is activated by amplification. Patients with neuroblastoma in which the MYC gene is amplified 10-300-fold have a poorer outcome. Point mutations can also activate proto-oncogenes. The NRAS proto-oncogene codes for a guanine-nucleotide-binding protein with guanosine triphosphatase activity that is important in signal transduction and is mutated in 25-30% of acute nonmyelogenous leukemias, resulting in a constitutively active protein. The RET protein is a transmembrane tyrosine kinase receptor that is important in signal transduction. A point mutation in the RET gene results in the constitutive activation of a tyrosine kinase, as found in multiple neoplasia syndromes and familial thyroid carcinoma.

The third mechanism by which proto-oncogenes become activated is by chromosomal translocation. In some leukemias and lymphomas, transcription-factor controlling sequences are relocated in front of T-cell receptors or immunoglobulin genes, resulting in unregulated transcription of the genes and leukemogenesis. Chromosomal translocations can also result in fusion genes; transcription of the fusion gene can result in the production of a chimeric protein with new and potentially oncogeneic activity. Examples of cancers associated with fusion genes include the childhood solid tumors like Ewing’s sarcoma [t(11;22)] and alveolar rhabdomyosarcoma [t(2;13) or t(1;13)]. The translocations result in novel proteins that are useful as diagnostic markers. The best described translocation in leukemia is the Philadelphia chromosome’s t(9;22), which results in the BCR/ABL protein found in chronic myelogenous leukemia. This translocation results in a tyrosine kinase protein that is constitutively activated. In addition, the protein is localized to the cytoplasm instead of the nucleus, exposing the kinase to a new spectrum of substrates.

Alteration in the regulation of tumor suppressor genes is another mechanism involved in oncogenesis. Tumor suppressor genes are important regulators of cellular growth and apoptosis. They have been called recessive oncogenes because the inactivation of both alleles of a tumor suppressor gene is required for expression of a malignant phenotype.

Knudson’s “two-hit” model of cancer development was based on the observation of the behavior of the RB tumor suppressor gene. In sporadic cases of retinoblastoma, both alleles of the RB gene must be inactivated. However, in familial cases, children inherit an inactivated allele from one parent, and consequently require the inactivation of the only remaining normal allele. This helps explain why familial cases of retinoblastoma occur earlier in childhood than sporadic cases, because only one “hit” is required.

Another major tumor suppressor protein is P53, which is known as the “guardian of the genome” because it detects the presence of chromosomal damage and prevents the cell from dividing until repairs have been made. In the presence of damage beyond repair, P53 initiates apoptosis and the cell dies. More than 50% of all tumors have abnormal P53 proteins. Mutations in the P53 gene are important in many cancers, including breast, colorectal, lung, esophageal, stomach, ovarian, and prostatic carcinomas as well as gliomas, sarcomas, and some leukemias. More than 170 putative tumor-suppressor genes have been identified.

Syndromes Predisposing to Cancer

Several syndromes are associated with an increased risk of developing malignancies, which can be characterized by different mechanisms (Table 486-2). One mechanism involves the inactivation of tumor suppressor genes such as RB in familial retinoblastoma. Interestingly, patients with retinoblastoma in which one of the alleles is inactivated throughout all of the patient’s cells are also at a very high risk for developing osteosarcoma. A familial syndrome, Li-Fraumeni syndrome, in which one mutant P53 allele is inherited, has also been described in patients who develop sarcomas, leukemias, and cancers of the breast, bone, lung, and brain. Neurofibromatosis is a condition characterized by the proliferation cells of neural crest origin, leading to neurofibromas. These patients are at a higher risk of developing malignant schwannomas and pheochromocytomas. Neurofibromatosis is often inherited in an autosomal dominant fashion, although 50% of the cases present without a family history and occur secondary to the high rate of spontaneous mutations of the NF1 gene.

Table 486-2 FAMILIAL OR GENETIC SUSCEPTIBILITY TO MALIGNANCY

ALL, acute lymphocytic leukemia; AML, acute myelocytic leukemia; GI, gastrointestinal; GU, genitourinary; JMML, juvenile myelomonocytic leukemia; NHPCC, nonhereditary polyposis colon cancer.

A second mechanism responsible for inherited predisposition to develop cancer involves defects in DNA repair. Syndromes associated with an excessive number of broken chromosomes due to repair defects include Bloom’s syndrome (short stature, photosensitive telangiectatic erythema), ataxia-telangiestasia (childhood ataxia with progressive neuromotor degeneration), and Fanconi anemia (short stature, skeletal and renal anomalies, pancytopenia). Due to the decreased ability to repair chromosomal defects, cells accumulate abnormal DNA that results in significantly increased rates of cancer, especially leukemia. Xeroderma pigmentosum likewise increases the risk of skin cancer, owing to defects in repair to DNA damaged by ultraviolet light. These disorders display an autosomal recessive pattern.

The third category of inherited cancer predisposition is characterized by defects in immune surveillance. This group includes patients with Wiskott-Aldrich syndrome, severe combined immunodeficiency, common variable immunodeficiency, and the X-linked lymphoproliferative syndrome. The most common types of malignancy in these patients are lymphoma and leukemia. Cure rates for immunodeficient children with cancer are much poorer than for nonimmunodeficient children with similar malignancies, suggesting a role for the immune system in cancer treatment as well as in cancer prevention.

Other Factors Associated with Oncogenesis