PRACTICAL GENETICS IN CANCER: THE HUMAN GENETIC CODE

by Eric P. Hoffman PhD Source: Spring 2000 CCCF Newsletter

Pediatric cancer families are more and more frequently presented with genetic information regarding their child’s disease. The genetic tests can sometimes hold important diagnostic and prognostic information. Genetic technology is continuing to develop extremely rapidly; for example the NIH has recently announced a program to provide a series of $8 million grants to use “gene microchips” to help diagnose cancer patients, and provide information on the likely responsiveness of specific patients to types of cancer therapy. This new type of large scale “genetic informatics” is expected to have a dramatic effect on how pediatric cancer patients are diagnosed, and treated.

This is the first of a series of “primers” that hope to help provide an understanding of current and future applications of gene technology to the diagnosis and care of children with cancer. This first article provides some perspective with regards to the genetic code of humans, and how this is frequently altered such that tumors result. The second installment will speak to current genetic tests in pediatric oncology patients, and what the results of these tests mean.

The last contribution will describe emerging high-tech methods which are being developed to provide “molecular fingerprints” of each child’s tumor, and how this will likely effect treatment of childhood cancer in the near future.

First, for some perspective. The genetic code which makes up all individuals is nothing more than a series of instructions to produce all the components of the body; from the time that the sperm and egg meet, to old age. There is a relatively accurate analogy with regards to the famous kitchen volume, the Joy of Cooking. Both the Joy of Cooking and the human genome consist of a relatively large series of recipes, one after the other, spelled out in code. The Joy of Cooking is considerably more complicated in that 26 letters are used, while the human genome uses only four (G, A, T, and C). As in any alphabet, the letters simply refer to some other meaning; in the case of DNA the letters refer to four specific chemical structures that can be hooked up into chains (as letters are hooked up into words and sentences), G = guanine base, A = adenine base, T = thymine base, C = cytosine base. A typical recipe in the Joy of Cooking contains about 30,000 letters of code, and this is quite similar to the average size of a gene (a recipe for a component of your body). A gene and a recipe are also similar in that they themselves are not particularly useful (you cannot eat a page of the Joy of Cooking), but contain the code to make something; the component of the body that each contains the instructions for producing is called a protein.

The entire human genetic code contains about 120,000 genes (3 billion letters), which is equivalent in number of letters and recipes to about 100 volumes of the Joy of Cooking. While this sounds like a fairly large number of recipes for proteins, there are many different parts of the body that change with age, so this is not so surprising. Importantly, it has recently been announced that 90% of this 3 billion letter genetic code will be available this coming Spring of 2000; we will all be able to go to our home computers and click over the entire instructions for a human being, just as you would go look up recipes for a thanksgiving dinner in the Joy of Cooking!

It is quite clear that cancer is the result of problems with this genetic code. There are two groups of genes that are responsible for most cancers, each of which causes a single cell to lose control, and become a tumor in a child, but using different methods. The two groups are “oncogenes” and “tumor suppressors”. Oncogenes, as the name implies, are genes which can directly cause cancer. Nobody is “born” with oncogenes; instead there are changes to pre-existing recipes that a single component (protein) of a cell from a normal, healthy part of the body, to something that “changes its function” so that it has a dominant effect on the cell; it effectively tells the cell to grow out of control (become a tumor). An analogy here is “the bad person in the neighborhood”; some one member of a large community loses control of his/her actions, and can wreak considerably destruction within the community. “Tumor suppressors” are like the policemen in the community; they constantly survey the neighborhood for problems, and keep things under control. Tumor suppressors are involved in tumors when they are missing from the cell. Thus, oncogenes and tumor suppressors are involved in cancer in opposite ways; it is the presence of an oncogene protein that causes a tumor, while it is the absence of tumor suppressors that leads to cancer. Here it is important to point out the issue of inheritance of cancer in families. Some childhood tumors can be inherited, such as retinoblastoma, although most are isolated “sporadic” cases. The retinoblastoma gene is a “tumor suppressor”, and all of us have two copies of the code for this “policeman”; one from our mother, and one from our father. What happens in families with retinoblastoma is that one of the two genes in a retinoblastoma patient is disabled (one policeman in the community instead of two). Generally, half of any component of your body is “enough”, and all cells are kept under control. However, a single cell can suddenly lose the other retinoblastoma gene due to environmental effects (cosmic rays), or just by chance. This cell has no remaining retinoblastoma protein, and loses all police surveillance, and goes out of control (becomes a tumor). The inheritance of retinoblastoma is via the passing along of the one disabled copy of the code to a child. Many adult cancers, such as breast cancer, and colon cancer, are inherited by a similar “two hit” mechanism. Oncogenes can generally not be inherited, because the production of a toxic protein so early in life would almost certainly not be compatible with the baby even being born.

There is a third type of cancer gene, namely those involved in repair of damage to genes; this group seems more important for human colon cancers, and not as much pediatric tumors. However, one can easily imagine that the gradual loss of the ability of a cell to repair damage to the code would result in the failure to correct changes to the code of oncogenes and tumor suppressors, which is precisely what happens.

In all tumors, it is often a series of genetic changes of both to create oncogenes, and changes to remove tumor suppressor genes. Precisely which events occur to which genes determines the type and aggressiveness of the tumor. Scientists and clinicians realize that only a small fraction of the changes are known for any tumor, although some specific changes clearly have a dramatic effect (for example, the new oncogene created with the Philadelphia chromosome translocation). It is the complexity of cancer which makes new high-tech approaches such as gene microchips so promising. These developments, and the specific gene changes associated with specific pediatric cancers, will be described in the next issues of the newsletter.

Dr. Hoffman has had a long-term interest in genetics and its implications for health and disease. As a post – doctoral fellow, he participated in the identification of the first ‘positionally cloned’ human gene and the identification of its protein product. He is currently Director of the Research Center for Genetic Medicine at the Children’s National Medical Center in Washington DC, Professor of Pediatrics at George Washington University (and is married to wife Ruth.)