Genetic Disorders - Cancer

Cancer is a large group of diseases characterized by uncontrolled cell division and the growth and spread of abnormal cells. These cells may grow into masses of tissue called tumors. Tumors composed of cells that are not cancerous are called benign tumors. Tumors consisting of cancer cells are called malignant tumors. The dangerous aspect of cancer is that cancer cells invade and destroy normal tissue.

The mechanisms of action that disrupt the cell cycle are: impairment of a DNA repair pathway, transformation of a normal gene into an oncogene (a hyperactive gene that stimulates cell growth), and the malfunction of a tumor suppressor gene (a gene that inhibits cell division). Figure 5.7 shows the multiple systems that interact to control the cell cycle.

The spread of cancer cells occurs either by local growth of the tumor or by some of the cells becoming detached and traveling through the blood and lymphatic system to develop additional tumors in other parts of the body. Metastasis (the spread of cancer cells) may be confined to a local region of the body, but if left untreated (and often despite treatment), the cancer cells can spread throughout the entire body, causing FIGURE 5.7
The cell cycle and cancer
SOURCE: "The Cell Cycle and Cancer," in Genetics, vol. 1, A–D, Macmillan Reference USA, Gale Group, 2002 death. It is perhaps the rapid, invasive, and destructive nature of cancer that makes it, arguably, the most feared of all diseases, even though it is second to heart disease as the leading cause of death in the United States.

Cancer can be caused by both external environmental influences (chemicals, radiation, and viruses) and internal factors (hormones, immune conditions, and inherited mutations). These factors may act together or in sequence to begin or promote cancer. There is consensus in the scientific community that several cancer-promoting influences accrue and interact before an individual will develop a malignant growth. With only a few exceptions, no single factor or risk alone is sufficient to cause cancer. As with other disorders that arise in response to multiple factors, susceptibility to certain cancers is often attributed to a mutated gene. Figure 5.8 shows how the inheritance of a mutated gene increases susceptibility for retinoblastoma (cancer of the eye that affects approximately 300 children in the United States each year).

Genetic Research

Scientists and physicians have known for some time that predisposition to some forms of breast cancer are inherited and have been searching for the gene or genes responsible so that they can test patients and provide more careful monitoring for those at risk. In 1994 doctors identified the BRCA1 gene, and in late 1995 they also isolated the BRCA2 gene. Since then it has been found that variations of the ATM, BRCA1, BRCA2, CHEK2, and RAD51 genes increase the risk of developing breast cancer, and the AR, DIRAS3, and ERBB2 (also called Her-2/neu) genes are associated with breast cancer.

If a woman with a family history of breast cancer inherits a defective form of either BRCA1 or BRCA2, she has an estimated 80% to 90% chance of developing breast cancer. Researchers also think that the two genes are linked to ovarian, prostate, and colon cancer, and BRCA2 likely plays some role in breast cancer in men. Scientists suspect that the two genes may also participate in some way in the development of breast cancer in women with no family history of the disease. Only FIGURE 5.8
Inheritance of a mutated retinoblastoma gene
SOURCE: "Inheritance of a Mutated Retinoblastoma Gene," in Genetics, vol. 1, A–D, Macmillan Reference USA, Gale Group, 2002 FIGURE 5.9
Location of the BRCA1 gene
SOURCE: "Where is the BRCA1 gene located?" in Genetics Home Reference, U.S. National Library of Medicine, 2004, http://ghr.nlm.nih.gov/gene=brca1;jsessionid=B9C5F23B7BFED46324978C8EC00D7DF1#location (accessed February 8, 2005) FIGURE 5.10
Location of the BRCA2 gene
SOURCE: "Where is the BRCA2 gene located?" in Genetics Home Reference, U.S. National Library of Medicine, 2004, http://ghr.nlm.nih.gov/gene=brca2 (accessed February 8, 2005) about 5% of all cases of breast cancer are attributable to the susceptibility genes BRCA1 and BRCA2. Figure 5.9 shows the locations of the BRCA1 gene on the long arm of chromosome 17 at position 2. Figure 5.10 shows the location of the BRCA2 gene on the long arm of chromosome 13 at position 12.3.

A November 1996 study headed by Stephen C. Rubin, a professor and chief of gynecological oncology (cancers of the female reproductive organs) at the University of Pennsylvania, reported a result that was totally unexpected. The study found that women with defective BRCA1 genes who developed ovarian cancer survived longer than those without the mutated gene who developed ovarian cancer. Women with the defective gene lived an average of seventy-seven months after diagnosis, while those without the mutated gene averaged only a twenty-nine-month survival. Researchers do not know if those with the defective gene had less deadly types of cancers or if their cancers responded better to treatment.

Another form of breast cancer, due to multiple copies of a gene called ERBB2, causes an estimated 25% of the approximately 180,000 new cases of the disease in the United States each year. ERBB2 often triggers an aggressive form of cancer that can cause death more quickly than other breast cancers, often within ten to eighteen months after the cancer spreads. The ERBB2 gene produces a protein on the surface of cells that serves FIGURE 5.11
Location of the ERBB2 gene
SOURCE: "Where is the ERBB2 gene located?" in Genetics Home Reference, U.S. National Library of Medicine, 2004, http://ghr.nlm.nih.gov/geneerbb2 (accessed February 8, 2005) as a receiving point for growth-stimulating hormones. Figure 5.11 shows the location of ERBB2 on the long arm of chromosome 17 between positions 11.2 and 12.

Herceptin, a genetically engineered antibody, increases the benefits of chemotherapy by shrinking tumors and slowing the progression of ERBB2. Herceptin became available in late 1998.