Connecting Concepts Across Chapters 9

This chapter has focused on three specialized but important topics: the genetics of development, the immune system, and cancer. In addition to their relevance to genetics, these topics have obvious medical importance and all are the subject of intense research.

The results of early experiments demonstrated that genes are not usually lost or permanently altered in the course of development; rather, development proceeds through the regulation of gene expression. The basic question for development is how are different sets of genes expressed in different parts of the embryo? Our study of pattern formation in Drosophila revealed that many genes take part and that they are regulated in a highly sequential manner. The process is initiated by maternally produced mRNA and proteins that become localized to particular regions of the egg. Sets of genes are successively activated, each set controlling the expression of other sets, so that successively smaller regions of the embryo are determined.

The immune system also is encoded by a complex set of genes whose products interact closely. Unlike those in pattern development, genes encoding antibodies and T-cell receptors are permanently altered in lymphocyte maturation. Lymphocytes violate the general principle that all cells contain the same set of genetic information.

Cancer also is influenced by complex interactions among multiple genes. Paradoxically, cancer is fundamentally a genetic disease, but most cancers are not inherited, because cancer usually requires somatic mutations at multiple genes. Even for those cancers for which a predisposition is clearly inherited, additional somatic mutations are required for cancer to arise. These mutations, each rare, accumulate because they provide the cell with a growth advantage.

This chapter has synthesized much of the information provided in preceding chapters. Gene regulation (Chapter 16) is the basis of development, the understanding of which also requires knowledge of genetic maternal effects (Chapter 5), transcription (Chapter 13), and translation (Chapter 15). The rearrangement of segments in genes of the immune system builds on our understanding of recombination (Chapter 12) and RNA processing (Chapter 14). Chromosome and gene mutations (Chapters 9 and 17) are essential to understanding cancer progression. Many oncogenes and tumor-suppressor genes control the cell cycle (Chapter 2), and predisposition to some cancers may be inherited as single-gene traits (Chapter 3). Cancer may also entail mutations in DNA repair genes (Chapter 17), genes affecting chromosome segregation (Chapter 2), and the regulation of telomerase (Chapter 12). Recombinant DNA techniques (Chapter 18) have contributed tremendously to our understanding of all of these processes.

Breast Cancer

The New Genetics

Scientists in a medical genetics program of a major university medical school enroll a 54-year-old woman with metastatic breast cancer into a research protocol. The patient reports that several of her maternal relatives have breast cancer, but no pathological specimens from affected relatives are available for verifying the diagnoses. The patient dies before research studies are completed.

The patient has two daughters who are identical twins. Shortly after her mother's death, one of the twins requests access to her mother's test results. She explains that she wants this information because it will help her learn whether she carries the same mutation that might have contributed to her mother's disease. She has been informed that laboratories will not test for a mutation in a person before the identification of a known cancer-causing mutation in another family member affected by breast cancer. She wishes to learn whether she has a mutation because she is considering a prophylactic mastectomy to reduce her risk of developing breast cancer.

The research team learns from the head of the Institutional Review Board that there are no legal obstacles to this request, because the legal rights of the mother are not being compromised — she is deceased. The deceased are not considered research subjects under existing federal regulations.

On discovering her sister's intentions to request her mother's results, the second twin objects to the release of their mother's genetic information and says that she does not want to know whether she has inherited a greater risk of developing breast cancer. However, she went on to say, there is no way that the information could be kept from her, because she would inevitably learn of her sister's decision to have surgery. What should the research team do?

The case raises questions that are common in genetic research and clinical care today. Because of the nature and complexity of the questions raised, many of them require interdisciplinary examination. The GenEthics Consortium (GEC) was formed to bring scientists, bioethicists, lawyers, genetic counselors, and consumers together to discuss ethical issues emerging from research associated with the Human Genome Project.

In the late 1 990s, the GEC convened to consider this particular case. In the course of their discussion, some members expressed the opinion that the clinical setting should focus on meeting the needs of the individual person, and the research setting should focus on gathering evidence to support a hypothesis. Others disagreed, arguing that the results of genetic testing in research settings often have clinical implications for subjects.

No explicit guidance was given by the mother, — should researchers release this information to a child who requests it? Some argued that the fact that the mother's DNA was being tested for mutations that are markers for breast cancer implies that the mother was not opposed to this type of testing. Some also stated that we can safely presume that the mother expected to share that information with her husband and children.

But whether children have a right to access the mother's test results was not the only issue that merited discussion. What should clinicians and researchers do when family members disagree about whether such information should be made available? Some felt that the sister who first came to the researchers with a request for her mother's

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