! ! ! In order to understand the genetic mechanisms of how genes cause cancer, it is important to review some basic genetic concepts.

Genes come in pairs, and work together to make a protein product. One member of the gene pair comes from the mother, while the other member is inherited from the father. Eggs and sperm are called "germ cells." When an alteration or mutation in a gene is present in the germ cells, it is referred to as a "germline mutation." When a germline mutation is inherited, it is present in all body cells. On the other hand, mutations that we are not born with, but that occur by chance over time in cells of the body are said to be "acquired." Acquired mutations are not present in all cells of the body, are not inherited, and are not passed down to our children. Acquired mutations are always involved in causing cancer. Germline mutations are involved in a small percentage of cases.! ! ! click image to enlarge! The formation of tumors basically results from cell growth that gets out of control. In the human genome, there are many di"erent types of genes that control cell growth in a very systematic, precise way. When these genes have an error in their DNA code, they may not work properly, and are said to be "altered" or mutated. An accumulation of many mutations in di"erent genes occurring in a specic group of cells over time is required to cause malignancy. The di"erent types of genes, that when mutated, can lead to the development of cancer are described below. Remember, it takes mutations in several of these genes for a person to develop cancer. What specically causes mutations to occur in these genes is largely unknown. However, mutations can be caused by carcinogens (environmental factors known to increase the risk of cancer). The development of mutations is also a natural part of the aging process.! ! oncogenes! These are altered forms of genes known as proto-oncogenes. Protooncogenes are responsible for promoting cell growth. When altered or mutated, they become oncogenes and then can promote tumor formation or growth. Properties of oncogenes include the following:!

! Mutations in proto-oncogenes are usually acquired. The exception is that mutations in the RET proto-oncogene can be inherited and cause a condition called multiple endocrine neoplasia type II.! ! Having a mutation in just one of the two copies of a particular protooncogene is enough to cause a change in cell growth and the formation of a tumor. For this reason, oncogenes are said to be "dominant" at the cellular level.! ! tumor suppressor genes! Tumor suppressor genes are genes normally present in our cells. When working properly, they control the processes of cell growth and cell death (called apoptosis). Through these processes, they can also suppress tumor development. When a tumor suppressor gene is mutated, this can lead to tumor formation or growth. Properties of tumor suppressor genes include the following:! ! Both copies of a specic tumor suppressor need to be mutated (both members of the gene pair) in order to cause a change in cell growth and tumor formation to occur. For this reason, tumor suppressor genes are said to be "recessive" at the cellular level.! ! Mutations in tumor suppressor genes are usually acquired. The two mutations in a tumor suppressor gene pair may occur as the result of aging and/or environmental exposures.! ! A mutation in a tumor suppressor gene can also be inherited. In these cases, a mutation in one copy of the tumor suppressor gene pair is inherited from a parent, and therefore present in all cells of a person (germline mutation). The mutation in the second copy of the gene (which is necessary for tumor formation and cell growth change) is acquired and usually occurs only in a single cell or a handful of cells. If the second "hit" or mutation occurs in a type of cell that needs this particular tumor suppressor gene to control cell growth, the process of tumor formation will begin. This mechanism is also known as the "two-hit theory."! ! Most of the genes associated with hereditary cancer are tumor

suppressor genes. Nonetheless, most mutations in tumor suppressor genes are not inherited.! ! DNA repair genes! During cell division, the DNA in a cell makes a copy or replica of itself. During this complex process, mistakes may occur. Mismatch-repair genes are DNA repair genes that correct these naturally occurring spelling errors in the DNA. When these genes are altered or mutated, however, mismatches (mistakes) in the DNA remain. If these mistakes occur in tumor suppressor genes or proto-oncogenes, eventually this will lead to uncontrolled cell growth and tumor formation. There are other types of DNA repair genes that repair errors in DNA that occur from mutagenic agents such as large doses of radiation. Properties of DNA repair genes include the following:! ! Mutations in DNA repair genes can be inherited from a parent or acquired over time as the result of aging and environmental exposures.! ! DNA repair genes require two mutations (both members of the gene pair) in order for the process of tumor formation to occur. For this reason, mismatch-repair genes are said to be "recessive" at the cellular level.! Remember that it takes mutations in several of these genes for cancer to develop. In most cases of cancer, all the mutations are acquired. In inherited cancer, one mutation is passed down from the parent, but the remainder are acquired. Because it takes more than a single mutation to cause cancer, not all people who inherit a mutation in a tumor suppressor gene, proto-oncogene, or DNA repair gene will develop cancer.