Cancer Genetics Genetics

Cancer Is a Group of Diseases Characterized by Cell Proliferation Cancer kills one of every five people in the United States, and cancer treatments cost billions of dollars per year. Cancer is not a single disease; rather, it is a heterogeneous group of disorders characterized by the presence of cells that do not respond to the normal controls on division. Cancer cells divide rapidly and continuously, creating tumors that crowd out normal cells and eventually rob healthy tissues of nutrients. The cells of an advanced tumor can separate from the tumor and travel to distant sites in the body, where they may take up residence and develop into new tumors. The most common cancers in the United States are those of the lung, prostate gland, breast, colon and rectum, and blood.

Tumor Formation Normal cells grow, divide, mature, and die in response to a complex set of internal and external signals. A normal cell receives both stimulatory and inhibitory signals, and its growth and division are regulated by a delicate balance between these opposing forces. In a cancer cell, one or more of the signals has been disrupted, which causes the cell to proliferate at an abnormally high rate. As they lose their response to the normal controls, cancer cells gradually lose their regular shape and boundaries, eventually forming a distinct mass of abnormal cells—a tumor.

If the cells of the tumor remain localized, the tumor is said to be benign. If the cells invade other tissues, the tumor is said to be malignant. Cells that travel to other sites in the body, where they establish secondary tumors, have undergone metastasis.

Cancer As a Genetic Disease Cancer arises as a result of fundamental defects in the regulation of cell division, and its study therefore has significance not only for public health, but also for our basic understanding of cell biology. Through the years, a large number of theories have been put forth to explain cancer, but we now recognize that most, if not all, cancers arise from defects in DNA.

Genetic evidence for cancer Early observations suggested that cancer might result from genetic damage. First, many agents, such as ionizing radiation and chemicals, that cause mutations also cause cancer. Second, some cancers are consistently associated with particular chromosome abnormalities. About 90% of people with chronic myeloid leukemia, for example, have a reciprocal translocation between chromosome 22 and chromosome 9. Third, some specific types of cancers tend to run in families.

Retinoblastoma, a rare childhood cancer of the retina, appears with high frequency in a few families and is inherited as an autosomal dominant trait, suggesting that a single gene is responsible for these cases of the disease.

Although these observations hinted that genes play some role in cancer, the theory of cancer as a genetic disease had several significant problems. If cancer is inherited, every cell in the body should receive the cancer-causing gene, and therefore every cell should become cancerous. In those types of cancer that run in families, however, tumors typically appear only in certain tissues and often only when the person reaches an advanced age. Also many cancers do not run in families at all and, even in regard to those cancers that generally do, isolated cases crop up in families with no history of the disease.

Mutations in a Number of Different Types of Genes Contribute to Cancer As we have learned, cancer is a disease caused by alterations in the DNA. There are, however, many different types of genetic alterations that may contribute to cancer. More than 350 different human genes have been identified that contribute to cancer; the actual number is probably much higher. Research on mice suggests that more than 2000 genes can, when mutated, contribute to the development of cancer.

Oncogenes and Tumor-Suppressor Genes The signals that regulate cell division fall into two basic types: molecules that stimulate cell division and those that inhibit it. These control mechanisms are similar to the accelerator and brake of an automobile. In normal cells , both accelerators and brakes are applied at the same time, causing cell division to proceed at the proper speed. Because cell division is affected by both accelerators and brakes, cancer can arise from mutations in either type of signal, and there are several fundamentally different routes to cancer.

A stimulatory gene can be made hyperactive or active at inappropriate times. Mutations in stimulatory genes are usually dominant because even the reduced amount of gene product produced by a single allele is usually sufficient to produce a stimulatory effect. Mutated dominant-acting stimulatory genes that cause cancer are termed oncogenes. Cell division may also be stimulated when inhibitory genes are made inactive, analogous to having a defective brake in an automobile. Mutated inhibitory genes generally have recessive effects, because both copies must be mutated to remove all inhibition. Inhibitory genes in cancer are termed tumor suppressor genes.

Many cancer cells have mutations in both oncogenes and tumor-suppressor genes.

Genes That Control the Cycle of Cell Division The cell cycle is the normal process by which cells undergo growth and division. Normally, progression through the cell cycle is tightly regulated so that cells divide only when additional cells are needed, when all the components necessary for division are present, and when the DNA has been replicated without damage. Sometimes, however, errors arise in one or more of the components that regulate the cell cycle. These errors often cause cells to divide at inappropriate times or rates, leading to cancer.

Control of the cell cycle The cell cycle consists of the period from one cell division to the next. Cells that are actively dividing pass through the G1, S, and G2 phases of interphase and then move directly into the M phase, when cell division takes place. Non-dividing cells exit from G1 into the G0 stage, in which they are functional but not actively growing or dividing. Progression from one stage of the cell cycle to another is influenced by a number of internal and external signals and is regulated at key points in the cycle called checkpoints. For many years, the biochemical events that control the progression of cells through the cell cycle were completely unknown, but research findings have now revealed many of the details of this process.

References Benjamin A. Pierce, 2010. Genetics: A Conceptual Approach, 4th Edition. 4th Edition. W. H. Freeman.

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