Breast Cancer Susceptibility and the BRCA I Gene
by La Shawn Alexander

The frequency of cancer occurrence in America is such that most people can anticipate having their family effected in some manner by the disease. Cancer has become almost commonplace in society. Consequently, the study of its development and incidence is the subject of numerous research projects. Of considerable interest is the phenomenon of genetic breast cancer susceptibility. Breast cancer is estimated to affect 1 in 10 women at some point during their lifetime (Penn Today, 1995). Epidemiological studies have shown that some forms of breast cancer may have inheritable factors. This is implied by the observation that a woman's risk was greatly increased if she had a mother or sister who dies as a result of the disease before age 50, or if more than one sister was affected, or if a family member had a bilateral breast cancer (Roberts, Science). This paper will explore the incidence of breast cancer in conjunction with the occurrence of a mutation in the BRCA I gene as related to a patient, Joyce, age 32. Joyce has a family history of breast cancer associated with an inherited germline mutation in the BRCA I gene. Her mother was diagnosed at age 37 and her sister has been diagnosed as well.

Researchers have linked an increased risk of breast cancer with inheriting a mutation in the BRCA I gene. One in 200 women inherits this defective gene, and those who do so face an 80% to 90 % chance of developing the disease (Science, 1993). Familial breast cancer has been linked to a mutation in the BRCA I gene on chromosome 17. Under investigation is the role of the BRCA I gene in the development of breast cancer. Also under stufy is the risk factor associated with being a carrier of a BRCA I mutation and the incidence breast cancer. Women with inherited BRCA I mutations are born with one bad copy. They need only to acquire one additional damaging mutation in a breast cell in order for breast cancer to occur. The median age of breast cancer diagnosis is 62. However, in cases where the BRCA I mutation is present the median age is 45.
Women who possess an altered BRCA I gene are more likely to develop bilateral disease (cancer in both breasts or a second primary cancer). BRCA I is believed to be significant because the gene is thought to be a tumor suppressor. Thus, a non-mutated BRCA I gene codes for a protein that regulates cell growth. The deletion of the gene product produced by BRCA I, may then be the influencing factor increasing tumor susceptibility. In order for breast cancer to occur, the BRCA I genes on both chromosomes must be damaged or deleted. In Joyce's sister inherited one mutation and only one somatic mutation was necessary in order for tumors to development.
Assessing the risk of familial breast cancer is complex partially because the disease is genetically heterogenic. A team of University of Pennsylvania investigators, led by Jeff Boyd, Ph.D., of the Gynecologic Oncology Division, recently confirmed a link between ovarian cancer and the inherited mutation of the BRCA I gene. For women with a BRCA I mutation, there is a 63% lifetime risk of developing ovarian cancer as compared to a 1-2% risk in the general population ( Penn Today, 1993). It is possible for a person to develop tumors through the spread of cancerous cells, from another part of the body, via the lymphatic system and the blood system. An increased risk of breast cancer has also been observed in families with other inherited syndromes; including the Li-Fraumeni syndrome, characterized by soft tissue sarcoma, breast cancer, leukemia, and mutations in the p52 tumor supressor gene on chromosome 17. Other genes being studied for their role in breast cancer include the retinoblastoma tumor suppressor gene, the HER-2/neu oncogene, and the NM23 metastasis suppressor gene (National Cancer Institute). In addition, cancer can be influenced by lifestyle as well as by genetics. Persons exposed to radiation are more at risk than those who are not; in this way the location of a person's home may increase cancer risk. A smoker's has a cancer risk that is 100 times higher than a non smoker, due to the numerous carcinogens in tobacco. Therefore, one must consider in these enviromental influences when assessing cancer risk.
Genetically, Joyce has a 50 % chance of inheriting the BRCA I mutation from her mother. The previous statement is based on simple mendalian genetics. Joyce may have inherited her father's gene, which is assumed to be wild type. In the event Joyce inherited the mutated gene, a somatic mutation in the complementary gene would be required before tumor formation could occur. The probability of a somatic hit disabling the complementary gene then determines Joyce's risk for breast cancer. There is a strong relationship between cancer susceptibility and the individual's lifestyle. The connection becomes very evident in the study of various forms of cancers and in the assessment of risk. There are many factors that can influence the breast cancer formation. A man can develop breast cancer due to a mutation in the androgen receptor gene on the X chromosome. The cancer apparently develops from a relative overexpression of estrogen, rather than from activation of a cancer-causing gene. These facts suggest that breast cancer is not sex- limited, and it is genetically heterogenic.
One long term goal of breast cancer genetic research is to find ways to correct or mitigate the damage done by genetic alterations. This strategy may be useful in developing new methods of treating or preventing breast cancer. In a more general sense, as scientists learn in greater detail about the genetic events that lead to cancer, they gain an improved ability to understand and potentially to control the disease. The investigation of familial breast cancer caused by a germline mutation is important, considering that the results could lead to new methods for the detection of breast cancer and perhaps point to new therapies to target malignant cells.
The final assessment of Joyce's risk for inheriting breast cancer should be based on more than just the chances of her inheritance of a BRCA I mutation. The nature of the disease is genetically heterogeneous; thus her personal risk assessment must also include her risk from other factors, both genetic and environmental.

Roberts, L., 1993. Zeroing in on a Breast Cancer Susceptibility Gene. Science 259:622-625

Cancer Information Service. The BRCA I Breast Cancer Susceptibility Gene. National Cancer Institute. //

Cancer Risk Evaluation program. Evaluating the Risk: the Breast cancer/Ovarian cancer gene. Penn Today. Vol. 5 No. 2 //