In 1909 a chicken virologist named Peyton Rous investigated a tumor growing on the back of a Plymouth Rock chicken that was brought to him by a farmer. Cancers are named for the type of cells in which they originate, and this tumor was a sarcoma, a tumor that grows in connective tissue and muscle. Rous found that he could transmit the tumor from chicken to chicken by injecting cancer cells into disease-free chickens. This was not surprising, but then he found a shocking result—he could grind up the cells and filter the cellular soup through very fine sieves until he had no cells to inject, but he could still transmit the cancer! This led him to conclude that a very small particle, called a virus, was transmitting the cancer, and this led to the idea that cancer was a viral disease. The virus was later named Rous sarcoma virus (RSV) and was the first virus known to cause cancer (16). However, RSV does not cause cancer in humans and, in fact, it is rare to find any viruses that can cause human cancer. The human papilloma virus (HPV) can cause cervical cancer, the Epstein-Barr virus (EBV) can cause a form of lymphoma cancer in sub-Saharan Africa, hepatitis B virus is associated with liver cancer, and an adult form of leukemia is caused by the T-cell leukemia virus, but that is about it. Fewer than 5% of human cancers are caused by viruses (17).

So, if RSV does not cause human cancer, why did I bring it up? RSV was later discovered to be a type of virus called a retrovirus, most well-known for the human immunodeficiency virus (HIV) that causes AIDS. A retrovirus has RNA (ribonucleic acid) for its genetic code instead of DNA (deoxyribonucleic acid). The “central dogma” of molecular biology was long thought to be that the flow of information goes from DNA to RNA to proteins, but retroviruses turn the process around. They infect cells and turn their RNA into DNA, which gets incorporated into the DNA of the host cell and then makes more viral particles. The critical issue is that it can sometimes capture a gene from the host and incorporate it into the viral genome and then transmit it to other cells. That is exactly what RSV does; in particular, it picks up a gene called src (pronounced “sarc”) for sarcoma. Src is an example of a cancer-causing gene called an oncogene.

Many years later, in 1977, Ray Erikson discovered that src is a gene that codes for a particular kind of protein called a kinase, whose function is to add a phos­phate group to other proteins at certain critical sites (16). It turns out that the function of cells is strongly dependent on the specific phosphorylation of many different proteins, and this regulates processes of cell growth. When the Rous sar­coma virus picks up src in its genome and then infects a cell, the src gene phos — phorylates proteins and causes unregulated cell growth—a hallmark of cancer.

In paradigm-shifting experiments for which they received the Nobel Prize, Harold Varmus and Michael Bishop showed that the src gene is present in all kinds of cells as a normal gene that they called a proto-oncogene (16, 17). But if src is a normal gene in cells, how does it cause cancer when it is transmitted into other cells? The specific src gene that was transmitted by RSV actually had a deletion at the end of the gene that made it into a hyperactive kinase that phosphorylated proteins without normal regulation. That, then, is what made src a viral oncogene.

Since viruses are not a major cause of human cancer, are oncogenes impor­tant in causing cancer? To answer this question, scientists took DNA from human cancers and used new tools in molecular biology to break the DNA up into small pieces and insert them into cells. Sometimes the DNA that is inserted can cause a normal cell to transform into a malignant cell, and the specific gene that was inserted can be identified. These genes that could transform cells were also called oncogenes, but the difference is that they were genes that came from human can­cers, not from viruses, so they were called cellular oncogenes. A large number (at least 70) of these cellular oncogenes have been identified in various cancers, and they play an important role in causing cells to transform from a normal cell into a malignant cell (18). These cellular oncogenes all come from normal genes (proto-oncogenes) that help regulate the complicated process of cell growth. In all cases, the cellular oncogenes are modified from their parental proto-oncogenes so that they are hyperactive in promoting cell growth. Normal cells go through a cell cycle; in the final stage, mitosis, each cell divides into two cells. Cells normally respond to a lot of signals and follow intricate biochemical pathways to decide whether to grow and divide, but cellular oncogenes short-circuit some of these pathways to drive the cell into division. If you imagine that a cell going through the cell cycle is like a car going around a racetrack, the oncogenes are like stepping on the gas so that the cell grows and multiplies rapidly.

There are several ways in which proto-oncogenes can become cellular onco­genes, and radiation can cause at least two of them. In some cases, a deletion of part of a gene can cause it to become activated without normal regulation, and since radiation is good at deleting sections of DNA, it can activate oncogenes in this way. Another way is by producing reciprocal translocations. Recall that these occur when two different chromosomes are broken but the wrong pieces are stuck back together by DNA repair (NHEJ), and the DNA is criss-crossed from the two chromosomes so that each chromosome contains part of the other chromosome. A famous example of this is known as the “Philadelphia chromosome,” which the cytogeneticist Janet Rowley discovered is a reciprocal translocation between chromosomes 22 and 9 so that a piece of chromosome 9 is on 22 and a piece of 22 is on 9 (19). This particular chromosomal rearrangement is commonly found in a cancer known as chronic myelogenous leukemia (CML). But how can that cause a problem, since the total amount of DNA and the genes are preserved? The prob­lem is that this exact fusion of pieces of different chromosomes creates a chimeric gene known as bcr-abl that makes a new kinase, which phosphorylates proteins and causes cells to grow abnormally. Another cancer known as B-cell lymphoma is caused by the reciprocal translocation of chromosomes 14 and 18. In this case, the gene that is activated is a gene called bcl-2 that prevents lymphocytes (white blood cells) from dying in the process called apoptosis, so they keep multiplying and cause cancer (17).