WHAT IS CANCER AND HOW DOES IT ARISE?
The ability to sequence genomes inexpensively has had enormous impact in medicine and helped usher in the new era of personal genomics. One of the areas of highest impact is cancer, which will strike 40% of men and women at some point in their lifetime.
The ability of each cell in our bodies to grow and divide is tightly controlled by genetic factors; most cells in our bodies either stop dividing all together after we reach adulthood or divide rarely. Cancer results from the loss of these controls, leading to cells that grow and divide uncontrollably. When caught early, cancer often can be managed successfully. If cancer is not detected and treated, however, it may spread to other sites in the body in a process called metastasis. If this occurs, the cancer typically becomes more difficult to treat and can often be fatal. Certain cancers, such as ovarian and pancreatic cancer are often caught late because symptoms are absent or mild until the disease has advanced, and, therefore, these cancers have higher mortality rates.
One of the underlying causes of cancer is genetic mutations that affect cell growth and division, also called cell proliferation. These mutations fall into two general categories: those that actively drive cell proliferation and those that remove the constraints on cell proliferation. Mutations that stimulate cell proliferation are typically dominant and affect one copy of a gene; the presence of another, normal copy of the gene does not offset or mask the effects of the mutation. These dominant mutations transform a normal gene with cancer-causing potential (called a proto-oncogene) into a cancer-driving gene called an oncogene. We also have a number of genes that encode factors that put the brakes on uncontrolled cell proliferation. These genes are called tumor suppressor genes and generally both copies of the gene must be mutated for a cancer-promoting effect.
In general, development of cancer requires mutations in several different genes—cancers have multigenic causation. This is because there are multiple mechanisms at work in normal cells to ensure that cell growth and division occur at the appropriate times in the proper locations. The body also has defense mechanisms to eliminate certain abnormal cells before they can become cancerous. For most cancers, it is generally believed that mutations accumulate sequentially during a person’s lifetime (Figure 1). The person remains healthy until they have enough mutation(s) that wipe out the compensatory mechanisms and thus allow neoplastic, uncontrolled growth. As a tumor continues to grow and the cells rapidly divide, additional mutations may occur that make the tumor more aggressive, for example, or more able to metastasize.
Figure 1. For many cancers, multiple mutations in proto-oncogenes and tumor suppressors are believed to be responsible for uncontrolled cell proliferation. These are generally thought to accumulate over time. Mutations in DNA repair and chromosome integrity genes such as MLH and BRCA1 are particularly deleterious because they can dramatically increase the rate at which cancer-causing mutations arise.
Many different mutation types may contribute to carcinogenesis. DNA mutations may be present at birth or may occur spontaneously during our lifetimes. Mutations that we inherit from our parents are termed “germline” mutations and are generally present in all the cells in our bodies. The term “germline” comes from the origin of these mutations in the germ cells—the sperm or egg. Germline mutations are responsible for the cancers that run in families that lead to high predisposition for cancer.
Mutations that one acquires during one’s lifetime are termed “somatic” mutations. Somatic mutations may result when an error is introduced into DNA during cell division or from DNA damage (e.g., damage resulting from exposure of DNA in skin cells to ultraviolet rays from the sun). Somatic mutations are not passed down from parent to child. Germline and somatic mutations can be single base changes, indels, and/or large structural variations.
One type of mutation that is common in many cancers is gene fusion. Gene fusions typically result from chromosome rearrangements that fuse a gene or its regulatory sequence to a proto-oncogene. This results in aberrant, continuous expression or activity of the protein product of the proto- oncogene and uncontrollable proliferation of the cells containing the gene fusion. The first fusion gene to be implicated in cancer was the BCR-ABL fusion, which is a hallmark of chronic myeloid leukemia and occurs in > 95% of cases. Several hundred different gene fusions have been implicated in a variety of cancers.