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* University of Arkansas for Medical Sciences, Department of Family and Preventive Medicine, Little Rock, AR 72205 and University of North Carolina at Chapel Hill, Departments of Medicine and Genetics, Chapel Hill, NC 27599
2 To whom correspondence should be addressed. E-mail: mckelvey{at}uams.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • BRCA • cancer genetics • familial cancer
Cancer is the end product of a series of DNA mutations that lead to a selective growth advantage for a particular clone of cells. Critical genes that usually regulate cell growth are the targets for such cancer-causing mutations and can be classified into three main groups: protooncogenes, tumor suppressor genes, and gatekeeper genes. Protooncogenes stimulate and regulate controlled cell growth and division. Tumor suppressor genes normally inhibit cell growth or initiate apoptosis. Gatekeeper genes maintain genomic integrity by detecting errors in the genome and correcting them.
How are mutations acquired?
These three classes of critical genes acquire mutations by three major mechanisms: environment, chance, and heredity. How we live and what we are subjected to affects our genes and our propensity for cancer. For example, there are links between ultraviolet light and skin cancer (1), human papilloma virus and cervical cancer (2), radiation exposure and thyroid cancer (3), and tobacco smoke and lung cancer (4). Does this mean that all people who smoke get lung cancer or that all people who sunbathe acquire melanoma? Certainly not, therefore, something other than environment must also influence risk.
A substantial proportion of people who develop cancer have no obvious risk factors and simple chance is at least partially to blame. The body's ability to faithfully replicate DNA is incredibly accurate, but errors do occur. A mutation occurs as a result of DNA replication errors once every 10 million base pairs. Proofreading mechanisms correct 99.9% of those errors (5). This means that only one out of every 10 billion base pairs is duplicated erroneously during DNA replication; however, because a diploid cell contains 
6 billion base pairs, a new mutation is likely to occur somewhere in the genome of a cell once every two divisions. This figure can be thought of as a background rate of mutation that environmental exposures increase. Normal metabolic processes in the body generate reactive species, such as free radicals, that continually damage our DNA. Therefore, a considerable proportion of human cancer results from chance accumulation of mutations in these critical growth-regulating genes. The maintenance of our DNA is an uphill battle; given enough time, cancer is a probable outcome regardless of environmental exposures.
A third way that we acquire mutations in critical regulating genes is by inheriting them. One of the most significant risk factors for cancer is a strong family history and there are 35 commonly recognized familial cancer syndromes (Table 1) (6). These syndromes, such as hereditary breast and ovarian cancer, are caused by inherited alterations in critical genes that predispose patients to certain types of cancer. The abnormal genes are uncommon in the population as a whole but, when present, are associated with a high risk of cancer (i.e., they exhibit high penetrance). Importantly, these syndromes may be recognized by family history and therefore provide the primary physician a chance to practice preventive medicine for the presenting patient and the entire family (7).
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Let us use breast and ovarian cancer as an example: 212,600 new cases of breast and 25,400 new cases of ovarian cancer are diagnosed each year in the United States (8). Approximately 5–10% are hereditary (9). Therefore, 20,000 cases of familial breast and ovarian cancer will occur this year in the United States. Approximately 84% of cases in high risk families are secondary to breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutations (10). Approximately 100,000 breast cancer survivors are at risk for subsequent malignancies because of inherited BRCA3 mutations (11–13), and the prevalence of BRCA1 and BRCA2 mutations in the United States is estimated to be 950,000 individuals (11,14,15). When we consider all 35 cancer syndromes in Table 1, it is readily apparent that the burden of disease from such inherited mutations is considerable. Thus, although the overall percentage of hereditary cancer is small (5–10%), the absolute number of hereditary cancers is large because of the common occurrence of cancer in the population.
What are the indications of a familial predisposition to cancer?
The family history is the most significant clue to a predisposition to cancer in the individual or family. However, ascertaining family history is time consuming and, unless physicians obtain adequate family information, they may miss patients with inherited cancer syndromes who could benefit from genetic evaluation (16–18).
Certain aspects of the family history are especially important in recognizing inherited cancer syndromes (Table 2). A large number of affected individuals is an obvious clue. Families with more than one generation of affected individuals as well as the presence of individuals with independently arising tumors, such as bilateral breast cancer, also raise suspicion. The incidence of cancer in older people is higher than in younger people because DNA alterations caused by harmful environmental exposures and chance mutations accumulate over time (8,19). Therefore, a young age at diagnosis of cancer in an individual or their family members is a critical clue to the existence of a familial predisposition to cancer. For reasons not well understood, clustering of specific tumor types in a family (Table 3), such as breast and ovary cancer or colon and uterine cancer, is another important clue to familial predisposition. Finally, any population that has reproduced in a relatively isolated manner may have a high prevalence of specific mutations that confer an elevated risk of cancer. For example, whereas the prevalence of BRCA1 and BRCA2 mutations in the general Caucasian population of the United States is 0.2%, individuals of Ashkenazi Jewish ancestry have a baseline prevalence of >2% for such mutations (15,20). Thus ascertaining a patient's ancestral history is critical to risk assessment.
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Why recognize high risk families?
If high risk individuals within families can be identified, patients may be motivated to change behavior. Prospective evidence indicates genetic counseling, and testing leads to increased surveillance for breast and ovarian cancer (11). Analysis of the Framingham Offspring Study found that mammography use was higher among women with a family history of breast cancer than among women without a family history (25). A study of colorectal cancer found that a recognized strong family history of cancer was associated with better adherence to sigmoidoscopy recommendations (26).
Recognition of high risk families is important because it alters medical management. Using BRCA1 and BRCA2 as an example, genetic testing may be offered to patients at high a priori risk of having a mutation. Finding a mutation provides opportunities to prevent hereditary cancer by chemoprevention and surgery. High risk women have chemoprevention options such as tamoxifen. The U.S. Preventive Services Task Force concluded that tamoxifen can significantly reduce the risk of invasive estrogen receptor–positive breast cancer in high risk patients; the likelihood of benefit increases as the risk of cancer increases (27). Data also suggest that prophylactic tamoxifen may reduce breast cancer incidence in healthy BRCA2-positive patients (28). Trials are underway to evaluate the efficacy of raloxifene, another selective estrogen receptor modulator, for breast chemoprevention.
Surgical options are available to decrease cancer incidence in BRCA1 and BRCA2 carriers. Prophylactic oophorectomy reduces ovarian cancer risk by >90% and reduces breast cancer risk by >50% if done before age 50 (29–31). Properly timed oophorectomy is also advisable because we have no effective screening for ovarian cancer because pelvic exams, CA-125 levels, and transvaginal ultrasound are of highly questionable efficacy (32–34). Prophylactic mastectomy reduces breast cancer incidence by at least 90% in women with moderate-to-high risk and is a viable option for the prevention of breast cancer in women who are willing to undergo this significant intervention (35).
Breast-conserving therapy has become the standard of care for eligible women diagnosed with breast cancer in the United States. However, for BRCA1 or BRCA2 mutation carriers, bilateral mastectomy is increasingly recommended as the optimal treatment modality because of the 70% chance of another breast cancer in the ensuing 10 y if breast-conserving therapy is pursued (36).
The effect of a negative test for cancer predisposition should not be overlooked in the appropriate setting. Test sensitivity and specificity is virtually 100% when a known mutation exists in the family. Therefore a negative test brings the patient's individual risk to that of the population at large and may alleviate anxiety as well as the psychological and monetary costs of excessive screening, unneeded medication, and surgery. A negative test also has important implications for the patient's children and future generations who will not inherit the mutated gene.
The recognition of high risk families and the molecular basis of the high risk has contributed greatly to our understanding of cancer in the general population. Increasingly, evidence suggests that subtle changes in the genome (polymorphisms) contribute to increased risk for common cancers. The time may soon approach when patients will be able to learn of their cancer predispositions through analysis of numerous genomic alterations that in isolation are subtle in their effect yet in totality have a substantial influence on risk of cancer and subsequent prevention strategy.
How are predictive genetic tests different from conventional medical tests?
Predictive genetic tests (PGTs) are emblematic of a new era of molecular medicine (37). They differ from traditional medical tests in part because they directly affect other individuals who may not have wanted such information. Most tests done in medical offices, such as electrolyte tests, throat cultures, or chest X-rays, have few implications for related family members. This is not the case for genetic tests. If a family member tests positive for BRCA1 or BRCA2, all first-degree family members are at a 50% risk of carrying the same mutation. Second-degree relatives are at a 25% risk, and so on. Depending on family size, the number of possibly affected family members can be quite large and the risk is never trivial. The fact that the content of your genes may directly affect the medical management of your mother, daughter, or sister is a new concept in medicine and carries with it a new set of ethical dilemmas.
Another way in which PGTs differ from traditional medical tests is the time frame they span. Traditional medical tests typically ascertain an individual's condition at that moment whereas genetic tests purport to reveal something about a possible future state or condition. Strictly speaking, predictive tests are not new in medicine. Cholesterol levels have been used for years to predict cardiac disease, and nuclear imaging routinely guides the need for further intervention in patients with chest pain. However, genetic testing presents a new set of conditions and new levels of complexity and uncertainty not found in traditional predictive tests. For example, even though a patient may carry a mutated gene, the precise nature and position of the mutation in the gene as well as other modifier genes affect future risk (10,38–40). Moreover, despite our rapid advances in genetic technology, our DNA code will remain unalterable for the foreseeable future.
Unlike a cholesterol level or a pap smear, a PGT directly examines one's unique genetic code and thereby addresses our individuality on a deeper level. Information about our genome is often seen as a special entity that can potentially be abused. Fears of genetic discrimination are widespread and the frightening concept of genetic determinism is reflected in media treatment of DNA technology, as evidenced by movies such as GATACA. At least partly for these reasons, genetic information is typically accorded a privileged position with respect to privacy and informed consent.
How is a PGT carried out?
Technically, a PGT is the search for alterations in one's genome that are associated with an increased risk of disease. The fundamental problem making such testing expensive and time consuming is the sheer size of the genes that need to be examined in a given test. For example, to assess breast and ovarian cancer risk in a woman with a strong family history, over 20,000 individual nucleotides need to be examined in the coding and relevant noncoding regions of BRCA1 and BRCA2. Although robotics and high throughput sequencing greatly speed sequencing, the process remains expensive and laborious. Commercial sequencing of these two genes costs $2400 and takes 3–4 wk for results. Although there exist screening methods such as protein truncation and single-stranded conformational polymorphism analysis, the reduced sensitivity and specificity are limiting factors and the current gold standard for mutation detection remains sequence analysis. The necessary pretest and posttest counseling that must accompany such testing is best measured in hours, not minutes.
What are the possible results and implications of genetic testing?
Continuing our example of BRCA1 and BRCA2 analysis, three possible outcomes exist whenever predictive genetic testing is carried out: a mutation is found, no mutation is found, or a polymorphism of unknown significance is found. It is critical to discuss these possibilities with patients before testing, and formal genetic counseling is a necessity.
Finding a mutation in BRCA1 or BRCA2 is informative but is not a guarantee that the patient will get cancer; a positive result simply increases relative risk. There is a 50–85% lifetime incidence of breast cancer and a 15–40% lifetime incidence of ovarian cancer in BRCA1 and BRCA2 mutation carriers (41–43). The penetrance of a mutation likely varies with its position in the gene, the environment, chance, and the effect of modifier genes. The preventive options previously discussed are applicable when a mutation is found. A positive test may also raise ethical, legal, and social issues as it relates to other family members who may also be affected.
A negative result when no BRCA1 or BRCA2 mutation has previously been identified in the patient's family is more problematic because the sensitivity of predictive genetic testing falls well short of 100%. Thus, a negative test implies one of two possible realities: the test is truly negative and the patient is at population risk or the test is a false negative and the patient is actually at high risk but we cannot find the responsible mutation because of limitations in current technology. The optimal setting in which to perform BRCA1 and BRCA2 analysis is when a familial mutation has already been identified. In this case a positive result specifies that the patient is at increased risk for cancer whereas a negative result is reliable, highly reassuring, and tells us that the patient did not inherit the familial mutation and is therefore at population risk for development of breast and ovarian cancer.
In the absence of a known familial mutation, false negatives occur and test results should be viewed with caution. For direct sequencing of exons, test sensitivity is 90%; therefore 10% of mutations are missed. Most deletions, inversions, large rearrangements, and mutations in introns and distant regulatory regions are not found with current methods. Likewise, errors in other as-yet unidentified genes, such as BRCA3 or BRCA4 may exist but are currently undetectable. Thus, depending on one's a priori risk of carrying a mutation, a negative result may reduce one's risk of being a mutation carrier but the residual absolute risk may still be substantial. The high risk patient should understand that a negative result means current testing has not identified the cause of cancer in her family and that she still remains at some degree of elevated risk. Formal Bayesian analysis can be used to estimate the residual risk in such settings and is routinely used by geneticists and genetic counselors to counsel patients when interpreting such negative results.
An alteration of undetermined significance may be found. This finding is usually a single base pair change in BRCA1 or BRCA2 with unknown effect on breast and ovarian cancer risk. Such a result is found in up to 15% of tested individuals and can be unsettling to the patient and provider alike. Additional information from other family members and from women who carry a known deleterious mutation may be sought to determine the significance of the variant. In some cases more data need to be collected to interpret the result and determine medical management.
Controlling the genetic genie
Medical genetics is transforming the field of preventive medicine, and genetic status will increasingly inform us with regard to a patient's options for screening, surveillance, preventive procedures, and treatment options. As preventive medications improve, genetic testing will have greater clinical utility but the gap between our ability to assess risk and our ability to actually alter that risk will remain or will widen. Predisposition genes will undoubtedly be identified much more rapidly than will the evidence-based outcome data to tell us how to properly use this burgeoning genetic information for the benefit of our patients. Direct-to-consumer advertising for predictive genetic tests is increasing in number and scope and presents new challenges to an already stressed health care system. These advertisements target naïve consumers with complex genetic information that is not easily reduced to a 30-s sound byte or brief print advertisement (44). Informed primary care providers are necessary to counsel patients and correct patient expectations.
Many questions remain unanswered and evidence is limited concerning behavioral responses to assessment of genetic risk (45). Will placing people into low, average, medium, or high risk groups be instructive to the patient and cost-effective to the population? Will it affect insurability? Some argue that placing people in average population risk groups may lead to complacency about health-promoting behaviors. Others maintain that targeting high risk patients for prevention efforts could prove to be cost-effective at a population level (46). Will personalized DNA evidence convince patients to alter long-term behavior to alter morbidity and mortality in a way that our past exhortations have failed to do?
Many ethical, legal, and social issues are unresolved. What you know about your DNA affects your family members. Who should view and control your genetic information? Who owns your genome, and along with that ownership, who holds the responsibility to inform at-risk family members? For example, if your father has a mutation in his APC gene, which portends a near 100% chance of colon cancer (preventable with colon resection at an early age), should he make that information available to you? If you have a specific mutation in your RET oncogene, which leads to medullary carcinoma of the thyroid, a potentially lethal cancer curable by surgical resection in its early stages, should you tell other family members of your DNA mutation? Should you be held liable if you do not share this information? Is your physician obligated to tell your family members? Should your physician be held liable if she does not share this information? Where is the line between a physician's duty to warn others and patient confidentiality? The answers to such questions are largely unsettled and case law varies from state to state. The educated opinion of health care providers will be crucial as the debate continues.
Court decisions have been conflicting with regard to ownership of genetic information and duty to warn (47). Federal legislation addresses genetic information and privacy to a limited degree but no broad legislation is in place. Although >40 states have enacted legislation to prohibit genetic discrimination in the workplace and with respect to health insurance, the legislation varies wildly from state to state in its comprehensiveness and quality.
If used wisely, predictive genetic testing can be a boon to the health of our patients. Discovering the genetic etiology of disease will accelerate our understanding of pathophysiology and lead to new and more effective treatments as recently demonstrated for chronic myelogenous leukemia (48–50). Predictive genetic testing will increasingly allow us to tailor screening strategies and treatment protocols to the individual instead of practicing a one-size-fits-all medicine as we do today. However, obstacles to the successful application of the new genetics loom. The supply of genetics professionals is inadequate for increasing demand (51) and the expansion of genetic knowledge will cause the primary care physician to be increasingly called on to provide genetic services (52). The judicious use of this new technology and its application in the context of well-informed providers and patients is essential to prevent harm in this new era of molecular medicine. We are looking at the tip of a great iceberg and it is our job to ensure that we harness its power instead of letting it sink the ship.
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FOOTNOTES |
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3 Abbreviations used: BRCA, breast cancer gene; PGT, predictive genetic test.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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