THE GENETIC DIAGNOSIS OF CANCER: THE QUESTIONS CONTINUE TO MULTIPLY

Elmer Kellmann
1992 Woodrow Wilson Biology Institute


Purpose and Background

Purpose:

There are three parts to this activity. First, it will provide the students with an opportunity to review some of the basic concepts of genetics, such as Mendelian inheritance and pedigree construction and analysis. Second, this activity will use recent findings in cancer genetics to present the information for the students to use. Finally, the students will use a pedigree in a "real life" situation, much like a genetic counselor. By using the role of a genetic counselor and/or a patient, the student will be faced with some of the ethical dilemmas that may arise from the genetic diagnosis of cancer.

Grade Level:

This activity could be used in various levels of Biology, grades 9-12. The students will have had Mendelian genetics and pedigree construction and analysis.

Objectives:

At the end of this activity the student will be able to:

  1. Construct a pedigree given the proper information about the family.

  2. Explain why a mutation in p53 gene may lead to a higher risk of cancer.

  3. Analyze a pedigree and make predictions and interpretations based on a pedigree.

  4. Analyze ethical dilemmas that may arise from the results of mutation in the p53 gene.

Materials:

The only materials needed for this activity are copies of the student activity pages. If the teacher desires more detail for the students (AP Biology for example) he or she may decide to use some of the articles cited in the bibliography.

Procedures:

The teacher will hand out the students pages of the activity. Depending upon the background of the students, the teacher will give as much or as little additional information he or she feels the students will need.

Evaluation/Conclusion:

The evaluation of the activity will involve checking the accuracy of the student responses to the questions. The dilemma questions will be evaluated at the discretion of the teacher. The answers should demonstrate that the students were following one of the decision-making models included with this module.

Background Information:

The word cancer is too familiar to many people. Almost everyone has had a relative or friend die as a result of cancer. Many people are even afraid to say the word and some fear being around someone who has cancer. They know it is not contagious, but why take a chance. If my father or mother has cancer, am I more likely to get this disease? Questions and fears surround cancer.

First of all, cancer is not a single disease but is a general term given to many different diseases. At the very basic level, all cancers have one thing in common-cells are dividing out of control. These cells usually have no function but they simply begin to crowd out healthy cells and rob those cells of needed nutrition. Research into the causes of cancer has been going on for may years and while progress has been slow, cancer is beginning to give up some of its secrets.

In 1986 it was demonstrated that at least one type of cancer could be inherited: retino-blastoma (cancer of the retina of the eye). The gene involved in the development of this cancer is called the retino-blastoma sensitive gene. This is a type of tumor suppresser gene. If a child inherits an abnormal (mutated) form of gene, then there is a 95% chance that the child will develop cancer of the retina.

What makes the tumor suppresser genes so important? Our body is composed of trillions of cells. Some cells, skin for example, divide frequently, replacing those being sloughed off the surface. Some cells, such as nerve cells, may never divide once they have been produced. There must be something that controls the rate at which these cells divide. Scientists have found that this "something" is a protein that is produced by a type of gene called tumor suppresser genes. If a mutation causes a change in the gene, that amount of protein produced is decreased and the division of the cell is no longer controlled. Cancer is the result.

Remember, there are two copies of each gene in the cell. For the tumor repressor gene, as long as one gene functions normally, the cell will remain under control. Therefore the mutated form of the gene is recessive. Why then is someone who inherits one gene much more likely to get cancer? Every cell in that individual's body has only one good tumor suppresser gene. If something in the environment, such as UV radiation, smoke, or chemicals damages the remaining tumor suppresser gene on one cell, that cell will no longer have its control mechanism and a cancer may develop. So, although the mutation is recessive, having only one copy of the normal gene puts the individual at much higher risk of developing cancer than someone who has both normal genes.

With the new technologies of molecular biology it is now possible to genetically screen individuals for certain genetic diseases. By removing a sample of blood and analyzing the DNA from the white blood cells, researchers can identify which form or forms of a gene an individual has in his or her cells. As a result, an individual can learn if he or she has the mutated form of a gene for which a test has been developed.

In 1990, another gene known as the p53 gene was associated with various inherited forms of cancer. This gene has also been classified as a tumor suppresser gene but it is different from the retinoblastoma sensitive gene in two very important ways. First of all, the retinoblastoma gene affects primarily the eye. If, through genetic screening, the individual has been diagnosed as having the mutated gene, the eyes can be carefully monitored by the physician. If a tumor begins to develop, it can be treated and there is almost a 100% survival rate. This is not the case with the p53 gene. Individuals with the mutated gene have approximately a 50% chance of developing cancer by age 30, not 95% as in retinoblastoma. Also, the tumors can begin to develop anywhere, so it becomes much more difficult to monitor the individual for the development of tumors. Finally, the success of the treatments for the types of cancers associated with p53 varies tremendously. In some cases treatments have little if any effect.

A word of caution-the p53 gene has been associated with only a very small number of cancers. This is not a means of screening for all types of cancers. As time goes on, perhaps the p53 mutation will be linked with more types of cancer but meanwhile this is simply one more small step on the journey to the causes and cures for cancer.


Problems:

  1. As a genetic counselor, you have received the following information from the molecular biology lab regarding a family with a type of cancer that has been associated with the p53 mutation.

    Frank has two brothers and two sisters. Both of Frank's parents are still living and appear to be very healthy. At age 18, Frank's brother George developed bone cancer, did not respond to treatment and died. Before he died a blood sample was taken and tested for the presence of the p53 mutation. Frank, his two sisters and both parents were also screened. The results are as follows:

    PersonMutation
    Present
    Mutation
    Absent
    Mother
    X
    FatherX
    GeorgeX
    Old sister Deb
    X
    Younger sister LindaX
    FrankX

    A. On a sheet of paper construct a pedigree of this family. Note that there are some changes in the construction of the pedigree. The individual with the mutated gene is indicated by placing a dot in the box or circle. If the individual has developed cancer, the box or circle is shaded. If the person has died, place a diagonal slash through the figure.

    B. Why do we not need to include a pedigree symbol for someone who is homozygous for the mutated p53 gene? Think carefully � use your background information.

  2. You have been given the following pedigree:

    Answer the following questions based on the above pedigree.

    A. Which individuals have a high risk for cancer? Explain your answer. In identifying the individuals, the Roman numeral indicates the generation and the Arabic numbers identify a particular individual within each generation.

    B. For individuals I-1 and I-2, what were the chances they would have had a child with the p53 mutation? What actually happened?

    C. If individual III-3 was planning to get married, what information could you give her regarding her children and their potential for developing cancer? Be sure your answer is complete. Your career as a genetic counselor depends upon a complete answer.

Think about and answer the following questions. They are not based on either of the above pedigrees.

  1. Charlie remembers when his family participated in the research program at the clinic. It was right before his fifteen year old younger sister died from cancer. Because he did not really know (nor did he really care) what was going on, he signed a form saying he did not want to know the test results. He recently read an article about the p53 gene mutation in the "Wall Street Journal" and now he understands what the testing was all about. Should Charlie contact the genetic counselor and ask to see the test results?

  2. Should the genetic counselor show Charlie the results?

  3. Charlie and the counselor, Ms. Wu, agreed to meet. After carefully explaining to Charlie what the test was all about, Ms. Wu told him that he did not have the mutation. During the course of the conversation, Ms. Wu answered the telephone. While she was talking on the phone, Charlie was able to see the pedigree of his family on the disk. He immediately noticed that his 50 year old father and this 21 year old brother both had the p53 mutation! They both seemed to be very healthy. Should Charlie tell his father and brother what he found out?

  4. You are Charlie's brother Carl. You have found out about the p53 mutation from your brother. You are filling out a job application for the position you have been dreaming about and you feel confident you will get the job. You come to a question which reads, "Are you aware of any health conditions that may affect your ability to perform your job?" How would you answer that question?

A CASE STUDY*

The 42 year old mother of Sam Jones has just been diagnosed with breast cancer. Sam's father was killed several years ago in an automobile accident. His father's brother has been suffering from prostate cancer for the past five years. Sam has a 14 year old younger brother and a sister who is married and has one child. She and her husband are contemplating having a second child to complete their family.

Sam intends to marry Sue Ellen, and hopes someday to have a family. The question that disturbs Sam is whether he has the p53 mutation. If he does, he knows there is a 50% chance that he may someday develop cancer. Moreover, there is a 25% chance that his children may inherit the defect from him, presuming that Sue Ellen is free of the mutation.

Some questions:

  1. Should Sam have the genetic screening test for the p53 mutation?

  2. Should Sam talk to his sister about the possibility of her having the mutation?

* Adapted from a case study by Dr. George Kieffer.


TEACHER NOTES - THE GENETIC DIAGNOSIS OF CANCER

Background:

As our ability to screen people for genetic diseases becomes more and more common, it is important that students have a basic understanding of how genetic screening works. Pedigrees are a way of visualizing the results of genetic testing for the individual and what effects it may have on the family. In addition, the ability to show someone his or her genetic profile will undoubtedly force upon that individual some rather difficult choices and/or decisions that must be resolved.

This activity is based upon the relatively recent discovery of a gene that has been linked to some forms of cancer. The p53 gene is a tumor suppresser gene. If one of the two alleles is mutated, the individual will be at a much higher risk of developing certain types of cancer. If this mutation occurs in the egg or sperm, then the gene can be passed on to the offspring in Mendelian fashion. The questions then arise. Do you want to know if you are at a higher risk to develop cancer? Can anything be done to prevent the development of the cancer? Who should have access to this information � employers, insurance companies? These are the questions that seem to be multiplying as fast as cancer cells themselves.

More detailed information will be given in the Student Background Information. Also, the bibliography section will list many articles for further reading.


Teacher Prep Notes:

The students need to be familiar with basic Mendelian genetics because the p53 mutation is inherited as an autosomal recessive gene. Also, the students need to be familiar with the construction and interpretation of pedigrees. The activity would best be used at the end of a unit on human genetics.

The last four questions are designed to show the students how a knowledge of some very basic genetic concepts will give them the factual information needed to deal with certain rather complex ethical dilemmas. These bioethical dilemmas are best dealt with by using some type of decision making model. A few of these models are presented at the beginning of this module. For the students to benefit the most from these problems, they should be familiar with one of these models or another model the teacher might choose to use.

Answers To The Problems

  1. A. The pedigree should resemble the one shown below. If the students are not familiar with the system for indicating generation and individual, this concept is introduced in question 2-A.

    B. The students should be able to answer this question if they put some thought into it. The p53 gene is always helping to control the rate of cell division. If each parent contributes a defective p53 gene to the zygote, development will not be able to continue because the cell division will be out of control. So a zygote with both recessive mutant genes has inherited a lethal defect and development will not occur.

  2. A. Individuals II-5, III-1, and III-3 are at high risk of developing cancer. Each one of these individuals has inherited a defective p53 gene from her parents and has a 50% chance of developing cancer by age 30.

    B. There was a 50% chance they would have had a child with the p53 mutation. 75% of their children were born with the mutant form of the gene.

    C. If individual III-3 was getting married, at the very least she would have a 50% chance of having a child with the mutated gene. An individual with a defective gene has a 50% chance of developing cancer before the age of 30. (Therefore she has a 25% chance of having a child who will develop a cancer before the age of thirty.) All of this assumes she marries a man who is homozygous for the normal gene. If the man she marries is heterozygous, there is a 67% chance that any child she has will inherit the gene. As a result, there is a 34% chance that any child she has will develop cancer before the age of thirty. Emphasize that this mutation has only been associated at this time with a small percentage of the total number of cancers that have been reported.

The four ethical dilemmas that are presented could be answered by individual students or in group discussion. Note that it is important that the students have some type of guidance to help order their thinking. The use of the decision-making models is highly recommended for this process.

The case study that is included could be an additional activity to be used as a class discussion.


References:

  1. "Identification of p53 as a Sequence-Specific DNA Binding Protein ", Scott E. Kern, Science, 21 June 1991, p. 1708.

  2. "Identification of p53 Gene Mutations in Bladder Cancers and Urine Samples", David Sidransky, Science, 3 May 1991, p. 706.

  3. "Testing for Cancer Risk: Tough Questions Ahead", Leslie Roberts, Science, 9 August 1991, p. 614.

  4. "p53 Mutations in Human Cancers", Monica Hollstein, Science, 5 July 1991, p. 49.

  5. "Genetic Mechanisms of Tumor Suppression by the Human p 53 Gene", Phang-Lang Chen, Science, 14 Dec 1990, p. 1576.

  6. "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and other Neoplasms", David Malkin, Science, 30 Nov 1990, p. 1233.

  7. "Studies Find Some Cancer Patients Have Inherited a Genetic Mutation", Michael Waldholz, The Wall Street Journal, 14 May 1992, p. B5.

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