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The Genetics Of Cancer

Cancer, by definition, is a disease of the genes. Cancer is also our most common genetic disease, but only rarely is it inherited. A gene is a small part of DNA, which is the master molecule of the cell. Genes make "proteins," which are the ultimate workhorses of the cells. It is these proteins that allow our bodies to carry out all the many processes that permit us to breathe, think, move, etc.

Throughout people's lives, the cells in their bodies are growing, dividing, and replacing themselves. Many genes produce proteins that are involved in controlling the processes of cell growth and division. An alteration (mutation) to the DNA molecule can disrupt the genes and produce faulty proteins. This causes the cell to become abnormal and lose its restraints on growth. The abnormal cell begins to divide uncontrollably and eventually forms a new growth known as a "tumor" or neoplasm (medical term for cancer meaning "new growth").

In a healthy individual, the immune system can recognize the neoplastic cells and destroy them before they get a chance to divide. However, some mutant cells may escape immune detection and survive to become tumors or cancers.

Tumors are of two types, benign or malignant. A benign tumor is slow growing, does not spread or invade surrounding tissue, and once it is removed, it doesn't usually recur. A malignant tumor, on the other hand, invades surrounding tissue and spreads to other parts of the body. The hallmark of a malignant cancer is the uncontrolled clonal proliferation and spread of abnormal cancer cells. If the cancer cells have spread to the surrounding tissues, then, even after the malignant tumor is removed, it generally recurs.

A majority of cancers are caused by changes in the cell's DNA because of damage due to the environment. Environmental factors that are responsible for causing the initial mutation in the DNA are called carcinogens, and there are many types.

There are some cancers that have a genetic basis. In other words, an individual could inherit faulty DNA from his parents, which could predispose him to getting cancer. While there is scientific evidence that both factors (environmental and genetic) play a role, less than 10% of all cancers are purely hereditary. Cancers that are known to have a hereditary link are breast cancer, colon cancer, ovarian cancer, and uterine cancer. Besides genes, certain physiological traits could be inherited and could contribute to cancers. For example, inheriting fair skin makes a person more likely to develop skin cancer, but only if they also have prolonged exposure to intensive sunlight.

Most cancers are sporadic and arise in a particular tissue such as the colon, breast, lung, or skin when normal cells acquire mutations in one or more oncogenes or tumor suppressor genes. The acquisition of multiple new genetic changes is what sets the cancer cell apart from the normal cells in its surrounding tissues.

The cancer cell develops when a normal cell in an organ or tissue acquires the capacity to divide in an uncontrolled fashion. Over time the developing cancer cell starts to multiply in a clonal fashion, begins to appear different (anaplastic or undifferentiated), and progressively acquires other characteristics, such as the capacity metastasise while losing cell-to-cell adhesion. The continued acquisition of new biologic characteristics is the key to many aggressive cancers evading the host defenses, and to the resisting some treatments such chemotherapy and radiotherapy.

It is important to appreciate that oncogenes and tumor suppressor genes are in fact normal cellular genes with vital functions within normal cells. It is only when they are mutated in some way that these genes become cancer causing.

The Ha-ras gene is a good example of an oncogene. Located on chromosome 11 at the normal cellular Ha-ras gene is one of a family of ras genes and encodes a small protein that is involved in intracellular signaling. Mutations in the ras oncogenes disrupt processing of cell signals and contribute to cell transformation. Mutations in ras oncogenes are found in approximately 10% of cancers especially cancer of the colon and lung.

The most important tumor suppressor gene is the p53 gene. This gene which is known as the guardian of the genome encodes for a protein with multiple intracellular functions related to the detection of DNA damage. When DNA is damaged by exposure to a mutagen such as UV irradiation the p53 gene is expressed. The p53 protein causes the cell to stop dividing so DNA mismatch repair genes can repair the DNA. If the DNA is successfully repaired, the cell resumes normal cell functions and the p53 gene is down regulated. However, if the DNA damage is beyond repair the p53 protein switches on a process called apoptosis (programmed cell death) leading to the death of the cell. For example, sunburn to the skin causes UV induced DNA damage, which often cannot be repaired. Expression of the p53 gene induces apoptosis the skin cells die and peel off.

Mutations in the p53 gene occur in approximately 50% of all cancers—particularly cancer of the breast, colon, lung, and brain. The mutant p53 protein is unable to stop uncontrolled cell division or switch on apoptosis, and can no longer protect the cell from acquiring additional mutation in other genes. The result is an unstable A transmission electron microscopy (TEM) of two spindle cell nuclei from a human sarcoma. Sarcomas are cancers of the connective tissue (bone, nerves, smooth muscle). Photograph by Dr. Brian Eyden. National Audubon Society Collection/Photo Researchers, Inc. Reproduced by permission. cell genome liable to further progressive DNA damage. The inherited cancer condition, Li-Fraumeni syndrome, is an autosomal dominant disorder caused by inherited mutations in the p53 gene. Individuals affected with Li-Fraumeni syndrome may develop breast cancer, brain tumors, leukemia, prostate cancer and various sarcomas at a young age.

Mismatch repair genes are another class of cancer gene contributing to instability of the cancer cell genome. Damaged DNA is repaired by an active DNA mismatch repair mechanism that identifies damaged DNA, then cuts out and repairs the the damaged DNA bases. Mutations in these repair genes are common in cancer cancers of the colon.

Oncogenes, tumor suppressor genes and other cancer causing genes can become mutated in any number of different ways. Most oncogenes become activated by specific mutations within their DNA sequence that causes the gene protein to function abnormally. Some oncogenes such MYCN are activated by DNA amplification. Oncogene amplification occurs commonly in neuroblastoma an aggressive cancer in children. These tumors can acquire hundreds of copies of this gene by DNA amplification making the cancer very resistant to treatment. Another means of oncogene activation is by its translocation from one chromosome to another. In the Burkitt lymphoma the c-myc oncogene is translocated from chromosome 8 to chromosome 14 where it becomes activated by an immunoglobulin gene. Only one allele of an oncogenes need to be activated for it to participate in cell transformation.

Tumor suppressor genes on the other hand are recessive and normally act to suppress cell replication. Cell transformation occurs when both gene alleles are inactivated (knocked out). Most commonly, inactivation of one gene allele occurs by a chromosome deletion. The second event may be an inactivating gene mutation, a second deletion or methylation of the genes promoter.

Regardless of the actual mutations involved a crucial concept in the development of most cancer is that more than one gene is usually involved in the process. Indeed in the development of cancer of the colon at least six or more separate oncogenes and tumor suppressor genes are involved in a progressive multi-step process to transform a normal colon cell into an aggressive, self replicating and invading cancer.

More recently, the application of gene expression arrays (microarrays) to the study of cancer has found that in addition to multiple gene mutations, the expression of many hundreds of non-mutant genes is affected in the process of cell transformation.

Microarray analysis of cancers of the breast and soft tissues has also identified distinctive patterns of gene expression which can be used to aid diagnosis and predict the clinical behavior of individual tumors.

This type of genetic analysis will also aid the development of new cancer therapies directed specifically at the molecular biology of the cancer.

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