Tumor Suppressors and Oncogenes

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The cell cycle is a series of ordered events that occur in a cell between it’s initial formation and eventual duplication and division into two daughter cells. Cells in the human body normally reproduce up to ~50 times [1], doubling their number with each cell cycle. Stem cells provide a pool of dividing cells to replace those that have died.

Interphase, the period between cell divisions, is where most cells remain for at least 90% of the cell cycle. Interphase consists of three phases: G1 (for gap 1), S phase (for synthesis) and G2 (for gap 2). During G1, the cell undergoes rapid growth and metabolic activity, including production of RNA and synthesis of protein. For the cell to divide and produce an identical copy of itself, its genome must be duplicated. DNA replication occurs in S phase. During G2, cell growth continues and the cell prepares for division. Cell division or mitosis occurs in M phase.

In normal cells, during G1 there are specific genes that control the speed of the cell cycle. These genes, called tumor suppressors and oncogenes, are mutated (meaning damaged) in cancer cells and can result in uncontrolled reproduction. Additionally, unlike normal cells, cancer cells do not stop reproducing after ~50 divisions. Thus, a cancer is an uncontrolled proliferation of cells.

Tumor suppressors

Tumor suppressors are genes that either slow down cell division, DNA repair or cell death (a process known as apoptosis or programmed cell death). These processes are all interconnected. Throughout the cell cycle there are DNA damage checkpoints; if there is damage, DNA replication is paused while the damage is repaired. In the event that the damage cannot be repaired, the cell initiates apoptosis. When a tumor suppressor gene is mutated (increasing either their expression or function) and inactivated (meaning turned off; also referred to as “loss of function”), cells can grow out of control and lead to cancer. As of 2003, 174 tumor suppressor genes were identified [2], including:

The analogy is often made between tumor suppressors and the brakes on a car. Just as the brakes keep a car from going too fast, tumor suppressors keep the cell from dividing too quickly.


In contrast to tumor suppressors that are inactivated, oncogenes are permanently activated. Oncogenes are mutated forms of genes called proto-oncogenes that normally control cell division and the degree of differentiation (a process by which cells acquire “a type”). When a proto-oncogene is permanently activated (meaning turned on; also referred to as “gain of function”) through mutation, it is called an oncogene. When this occurs, cell division happens too quickly and cells can grow out of control and lead to cancer.

Some classic examples of proto-oncogenes are:

Oncogenes are analogous to the accelerator on a car. Oncogenes “drive” the cell cycle, speeding up cell growth and division.

Two-hit hypothesis

In 1971, Alfred Knudson proposed the two-hit hypothesis for tumorigenesis [3]. While studying children with retinoblastoma (a cancer of the eye), Knudson noted differences between patients with inherited tumors and patients that appeared to have no susceptibility to the disease. Statistical analysis revealed that the fraction of cases not yet diagnosed in patients with the hereditary form of the disease decreased exponentially with age, suggesting that one mutational event caused the cancer.

His findings demonstrated that multiple mutational events or “hits” were necessary to cause cancer. Everyone has two copies of most genes, one from their mother and one from their father. Normally, one mutation is not enough for cancer to develop, unless you were born with it. This occurs with people who have familial cancer (meaning occurs in families). People who were born with a mutation in a tumor suppressor are predisposed to cancer and only need damage in the other copy for cancer to develop. Those born without the mutation require two mutational events to occur, statistically much less likely. However, there are cases where a single mutation is sufficient to cause an effect, notably the p53 gene.

The current view of cancer has built upon the two-hit hypothesis. Today, cancer is modeled as an accumulation of mutations in both tumor suppressors and oncogenes. Additionally, epigenetic changes (meaning something that affects a cell without changing its DNA sequence) [4] and microRNAs [5] play a role. Thus, a number of genetic and epigenetic alterations are thought to be required for tumor progression and the development of cancer.

The scope of this article is limited to a basic overview of the two general classes of genes that contribute to cancer. For a more information, Nature Milestones in Cancer highlights achievements made in cancer research since the end of the nineteenth century and provides historical perspective on how given concepts evolved.


  1. L Hayflick. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965 Mar;37:614-36.
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  2. Yang and Fu. TSGDB: a database system for tumor suppressor genes. Bioinformatics. 2003 Nov 22;19(17):2311-2.
    View abstract
  3. AG Knudson. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3.
    View abstract
  4. AP Feinberg. The epigenetics of cancer etiology. Semin Cancer Biol. 2004 Dec;14(6):427-32.
    View abstract
  5. Calin and Croce. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006 Nov;6(11):857-66.
    View abstract
About the Author

Walter Jessen, Ph.D. is a Data Scientist, Digital Biologist, and Knowledge Engineer. His primary focus is to build and support expert systems, including AI (artificial intelligence) and user-generated platforms, and to identify and develop methods to capture, organize, integrate, and make accessible company knowledge. His research interests include disease biology modeling and biomarker identification. He is also a Principal at Highlight Health Media, which publishes Highlight HEALTH, and lead writer at Highlight HEALTH.