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Gene Alterations and Cancer
The last 25 years of research have produced an explosion in our understanding of the nature and causes of cancer. In 1971, a handful of chemicals, viruses, and chromosome abnormalities were associated with cancers, but scientists did not understand what was happening inside the cell to cause cancer. Today, we know cancer is a genetic disease in which chemicals and viruses are a few of the many factors that cause mutations in our genes. When enough mutations accumulate in a cell, the normal processes inside the cell are disrupted, and tumors can begin to grow. Cancer occurs when mutations accumulate in two specific kinds of genes: those that encourage cell growth, known as oncogenes, and those that act as brakes on cell growth, called tumor suppressor genes. Mutated or excess copies of oncogenes result in altered or excess protein and too much cell growth. Mutations in tumor suppressor genes result in a protein that is missing or not working that fails to stop abnormal growth. Over 100 of these altered genes have been identified, and the normal cellular roles of many are known. This timeline highlights many key discoveries in the past 25 years that led to our current understanding of the link between gene alterations and cancer. Many of the human oncogenes mentioned in the timeline (src, ras, abl, myc, sis, erbB, erbA) were first discovered in animal tumor viruses. 1969 Normal cells are found to have genes that suppress the growth of tumors. When a rat tumor cell line was fused with normal cells, the tumor cells were no longer able to cause tumors in laboratory rats - showing that normal cells have genes that suppress the tumor cell genes. 1970 The first oncogene, now known as the src oncogene, is identified in a chicken tumor virus. The chicken virus, an RNA tumor virus discovered in 1911, was known to cause chicken tumors, but it was not known at the time that a specific gene in the virus caused the tumors. 1973 Cancer is linked to DNA exchanges between chromosomes. The chromosomes of patients with chronic myelogenous leukemia (CML) were found to have pieces of chromosome 9 and chromosome 22 exchanged. 1976 Oncogenes are discovered in normal DNA. The src oncogene (see 1970) was found in normal chicken DNA, showing that oncogenes do not have to come from outside the cell via a virus. This experiment suggested that a normal gene already present in the cell has the potential of becoming an oncogene. 1978 The Src protein is found to be a member of the protein kinase family of enzymes. This was the first clue to the function of an oncogene. Although the exact function of the Src protein was not known, this family of enzymes was known to be involved in cellular communications. 1979 The first human RNA tumor virus, HTLV-1, is discovered. The virus is associated with adult T-cell leukemia. (About 80 RNA animal tumor viruses from many species - chicken, mouse, rat, cat, baboon - had already been discovered; this was the first human RNA tumor virus.) 1981 Hepatitis B virus is associated with liver cancer. 1981 The first biologically active human tumor oncogene is identified from a human bladder carcinoma cell line. 1982 The 1981 human tumor oncogene is identified as H-ras, similar to an oncogene previously found in rat RNA tumor virus. 1982 DNA analysis shows that the difference between the ras oncogene and ras proto-oncogene (the normal gene before it is altered to become an oncogene) lies in a change in a single base (a subunit of DNA). 1982 The myc oncogene is found to be activated in Burkitt's lymphoma, a form of leukemia. This showed the association between cancer and an overproduced oncogene product. In the lymphoma, the oncogene becomes activated when it is transferred from chromosome 8 to chromosome 14. 1982 The abl oncogene is found to be activated in leukemia (CML) patients. This showed the association between cancer and an overly active oncogene product. In CML, when the oncogene is transferred from chromosome 9 to chromosome 22, the mutated Abl protein was found to be a fusion product - part of Abl is fused with another protein, making it much more active in the cell (see 1973). 1982 Several copies of the myc oncogene are found in human leukemia cells. This is the first evidence that an oncogene can become activated by having an excessive number of gene copies in a cell. 1983 The sis oncogene product is found to be a mutant form of a known protein, the platelet-derived growth factor (PDGF). This discovery provided the first link between an oncogene and a protein with a known function in the cell. 1984 The erbB oncogene product is discovered to be a truncated version of a protein (the epidermal growth factor receptor) that sits on the surface of certain cells. This discovery showed how a mutation in an oncogene can disrupt the normal function of the protein product. (The mutated ErbB protein was found to lack the part of the receptor that normally binds to molecules outside the cell.) 1985 Researchers discover that proto-oncogenes can function as transcription factors (proteins in the cell nucleus that regulate gene activity). The erbA oncogene product was shown to be similar to thyroid hormone receptors that were known transcription factors. 1986 The first tumor suppressor gene, Rb1, the retinoblastoma gene, is isolated. Genetic studies show that the development of retinoblastoma is due to inactivation of both copies of the Rb gene. 1988 An oncogene is associated with apoptosis, or programmed cell death. The Bcl-2 oncogene product, isolated from B-cell lymphoma, is shown to block programmed cell death in B cells. 1989 p53 is recognized as a tumor suppressor gene. Both copies of the p53 gene are inactivated in about 50 percent of cancers. (p53 was originally discovered in 1979 and thought to be an oncogene.) 1990 A rare familial cancer, the Li-Fraumeni Syndrome, is linked to mutations in both copies of the p53 gene. 1991 The APC (adenomatous polyposis coli) tumor suppressor gene, associated with hereditary colorectal cancer, is isolated. 1993 Several tumor suppressor genes associated with familial cancers are isolated: NF2, associated with acoustic nerve and brain tumors; VHL, associated with benign and malignant tumors in the kidney, retina, central nervous system, pancreas, and adrenal gland; and NTS-1/p16, a cell cycle inhibitor associated with malignant melanoma and pancreatic cancer. 1993 & 1994 Additional tumor suppressor genes associated with familial cancers are isolated: MSH-2 and MLH-1, associated with hereditary nonpolyposis colon cancer (HNPCC), are known to function normally in DNA repair; their mutated forms disrupt DNA repair. 1994 & 1995 Additional genes associated with familial cancer syndromes are isolated, including two tumor suppressor genes: BRCA1, associated with breast and ovarian cancer, and BRCA2, associated with breast cancer. One oncogene, CDK4, associated with melanoma, was also isolated; this proto-oncogene is a regulator of the cell cycle. In spite of the unprecedented inroads into our understanding of the molecular basis of cancer, extraordinary challenges remain. Researchers estimate that there are probably a hundred or more genes involved in cancers, in addition to the 100 already identified (about 80 oncogenes and 20 tumor suppressor genes). Also, most cancers involve mutations in several genes, and the patterns of genes that are altered in individual tumors and cancers have yet to be defined. The hope is that future cancer research will continue to build on the achievements of the past 25 years, and oncogenes and tumor suppressor genes can provide novel targets for the development of anticancer drugs.
The Cancer Information Service provides a nationwide telephone service for cancer patients, and their families, the public, and health care professionals. The toll-free number is 1-800-4-CANCER (1-800-422-6237); services are provided in English and Spanish. People with TTY equipment may call 1-800-332-8615. |
