Cancer Genetics

Other than skin cancer, breast cancer is the most common type of cancer among women in the United States. In 2003, an estimated 211,000 women will be diagnosed with breast cancer. In the vast majority of cases, 90% - 95%, breast cancer is not due to one gene alteration, or mutation, but results from environmental and genetic interactions. There may be more than one case of breast cancer in a family based on shared environment, similar lifestyles, shared genetic backgrounds, or sheer coincidence. However, a single inherited factor is believed to be responsible for about 5% - 10% of breast cancers, and there may be a pattern of cancers within some families that is suggestive of a cancer syndrome.

When several members of a family in many generations are affected with a particular type of cancer, especially at early ages, it is more likely that these family members share an inherited alteration in a gene which makes them genetically susceptible to cancer. This change only makes an individual predisposed to developing certain cancers, and some people who inherit the changed gene will not develop cancer. Since one in three people develops cancer at some point in his or her life, cancer can develop in several people in one family without there being an inherited mutation. It can be difficult to determine which familial cancers are due to inherited genes, which are due to shared environment and which are due to chance alone.

STRUCTURE AND FUNCTION OF BRCA1 AND BRCA2

The genetic basis of hereditary breast and ovarian cancer (HBOC) is a germline mutation in one of two known tumor-suppressor genes called BRCA1 and BRCA2. These genes have similar function in normal form, and therefore have similar dysfunction in abnormal form, although they are not inherited together and do not reside on the same chromosome (BRCA1 is on chromosome 17, while BRCA2 is on chromosome 13). They are rather large genes, with thousands of base pairs of DNA each. Normally the proteins encoded by these genes control unregulated cell growth (tumor suppressor genes) by signaling the cells to stop replicating when enough cells have been generated. If both copies of these regulatory genes are not functioning, the regulatory process of the cell cycle is disabled. If the cell growth mechanism is not regulated the cell can replicate without restriction resulting in tumor development.

Cancer development in this context is a two-step process involving mutations in both copies of the BRCA1 or BRCA2 gene. Mutations in BRCA1 or BRCA2 may be present in the germline or arise spontaneously as somatic alterations that are only present in the tissue in which they originated. A germline mutation is inherited in an autosomal dominant fashion, such that only one copy of the gene will be altered, although both copies must have mutations for cancer to develop. Therefore, the second mutation must be acquired sometime during the individual's lifetime. In a somatic cancer, the individual is not born with a BRCA1 or BRCA2 mutation. Mutations occur throughout the person's lifetime that predispose to cancer, and along with environmental or other factors can cause cancer to develop.

ASSOCIATED CANCER PREDISPOSITION

Mutations in the BRCA1 and BRCA2 are genes are known to increase the susceptibility to breast and ovarian cancer in individuals who carry them. Families with inherited cancer susceptibility due to an alteration in the BRCA1 gene may have multiple members with early onset breast and/or ovarian cancer. The lifetime risk for developing breast cancer for those carrying a mutation in the BRCA1 gene is thought to be in the range of 50% - 85%, and the ovarian cancer lifetime risk is approximately 20% - 40%. Studies are ongoing to refine these risks. In contrast, women from families without a hereditary component have a 10% - 11% lifetime risk for breast cancer and a 1% - 2% lifetime risk for ovarian cancer. Additionally, there may also be a small increased risk for prostate cancer in families with BRCA mutations. Families with a mutation within the BRCA2 gene have a similar breast cancer risk but the ovarian cancer risk is lower, probably on the order of 10% - 30%. There is also approximately a 6% risk for male breast cancer, and there may be an increased risk for other cancers, such as that of the pancreas.

RISK ASSESSMENT MODELS

Cancer risk assessment models can be utilized to help guide clinical judgement and patient management. Different cancer risk models can be used to help determine when to offer genetic testing, determine eligibility for chemoprevention, and offer patients accurate information about their individual risk. Current breast cancer risk models determine either 1) the patient's risk to develop breast cancer, or 2) the patient's risk to harbor a BRCA1 or BRCA2 mutation. A brief summary, including strengths and limitations of the more commonly used risk models are included below.

Genetic susceptibility testing is used to screen for alterations in the chemical sequence of a gene that could affect whether the gene will work properly. The preferred method of testing is to start with someone in the family who has been diagnosed with cancer, as it yields much more informative results. If a mutation in the family is known, then testing other family members is straight-forward and the results will be meaningful. If no mutation is known and an unaffected relative is tested, a negative result will be uninformative. This is due to the fact that not every genetic alteration is known and information about some discovered alterations is not complete. So the individual may have a mutation in the family that he or she did not inherit, which would be a true negative, or there may be no identifiable mutation in the family, which leaves the individual with an increased risk due to the family history that a negative result cannot negate. Finally, it is possible to find a variant of unknown significance, which does not provide a meaningful result. It is not known if it is deleterious or simply a polymorphism. As more people are tested and the technology is improved, the significance of the variation may be explained, but at present is not understood.

RISKS AND BENEFITS OF GENETIC TESTING

Benefits for those testing positive may include relief from uncertainty and the opportunity to plan appropriate medical management. Risks for those testing positive can include heightened anxiety and feelings of depression. Even though anxiety may already be present about the possibility of developing breast or ovarian cancer, this may become more acute when tangible evidence is available. Many individuals are also concerned that a positive genetic test result may result in insurance discrimination if an insurance company is requested either to pay for the testing or to reimburse for the additional medical management. However, legislation is in place to protect people from discrimination, especially in New Jersey, and while the concern is reasonable, no cases of discrimination based on genetic information have been documented to date.

Benefits for those testing negative include decreased anxiety and level of surveillance. Risks for those testing negative include altered family dynamics and the tendency to put off medical surveillance that is recommended to the general population.