" Second in a series of articles on genetics coordinated by Mary A. Curtis, MD, associate professor and director of clinical genetics, University of Arkansas for Medical Sciences, Little Rock. "

": Your distressed patient calls to tell you her sister was just diagnosed with stage I infiltrative ductal carcinoma of the breast. Her mother died at a young age, but accounts of the cause of death are varied. Another sister has "hyperplasia" of breast tissue. The question of genetic testing is weighing heavily on this woman's mind and heart. What should you tell her about genetic testing? Dr Elsas and Ms Trepanier offer help with this and other difficult questions associated with hereditary cancers."

"Elsas LJ II, Trepanier A. Cancer genetics in primary care: when is genetic screening an option and when is it the standard of care? Postgrad Med 2000;107(4):191-208"

"n the United States, cancer is likely to occur in one in two men and one in three women. All cancers stem from mutations in genes that carry the codes for tumor suppression or cell death (tumor suppressor genes), cell division or growth proliferation (oncogenes), and DNA repair. When functioning normally, these genes regulate cell growth and maintain DNA integrity. However, when several of them are mutated, the result is uncontrolled cell growth and, ultimately, cancer. "

" Most mutations are acquired by chance over a lifetime or occur as the result of specific environmental exposures. A subset of patients may be more likely to experience mutations in response to an environmental factor that causes subtle variations (polymorphisms) in several genes. However, in some families, predisposition to cancer occurs as the result of a single, germline (heritable) mutation in a tumor suppressor gene, oncogene, or DNA repair gene. This mutation is passed from one generation to the next. "

" Hereditary cancer follows an autosomal dominant pattern of inheritance. Each child of an affected parent has a 50% chance of inheriting the "cancer risk" mutation, but those who inherit their parent's normal (nonmutated) copy of the gene are not at increased cancer risk. Figure 1 (not shown) reviews the multistep nature of cancer development and the difference between hereditary and nonhereditary (sporadic) cancers. "

" How does the busy practitioner identify a patient with an inherited predisposition to cancer? The initial action should be to take a complete family history, collecting information on parents, siblings, daughters, sons, aunts, uncles, and grandparents, which can be formatted into a genetic pedigree. The history should include information about all types of cancer in both the paternal and maternal lineages. Ascertaining ancestry is also important. The essential questions to ask about relatives with and without cancer are listed in the box below. "

" If the family history reveals an early age of onset of cancer, a relative who had two or more independent cancers, two or more relatives with related cancers, or an incidence of rare cancers, the next step is to classify the significance of the history through pedigree analysis. At this point, referral to a genetic specialist might be appropriate. "

" Cancer in families is classified as sporadic, familial, or hereditary (figure 2: not shown). Classifying the history helps determine whether a patient is at increased risk of cancer, the degree of risk, and which organs are involved. Unfortunately, small family size, inaccurate patient reporting, and environmental factors, such as prophylactic surgery (false-negative history) or cigarette smoking (false-positive history), can complicate assessment. Accurate evaluation of family risk requires confirmation of cancer diagnoses from medical records; erroneous reporting among family members can lead to incorrect management (1). "

" In families with a significant history of cancer, DNA testing for germline mutations in cancer predisposition genes may help determine which relatives are at increased cancer risk. Unlike acquired mutations, heritable mutations are present in all cells of the body. Therefore, testing can be done on a blood sample. "

" Identification of a heritable mutation indicates an increased risk of a specific type of cancer. However, this is usually not a 100% risk, since other tumor suppressor genes or oncogenes in somatic tissues must be mutated before cancer can develop. "

" The likelihood that genetic testing will reveal a germline mutation in a cancer predisposition gene is highest in hereditary cancer, less likely in familial cancer, and unlikely in sporadic types. Therefore, pedigree analysis is important in deciding who may benefit from genetic studies. Genetic counseling about the benefits, limits, and risks of genetic testing (informed consent) is also an integral part of the process. An algorithm can be helpful for identifying, counseling, testing, and managing patients at increased cancer risk (figure 3: not shown). "

" Identification of genetic cancer risk offers several important clinical benefits for patients and their relatives. Because hereditary cancer often occurs at an earlier age than sporadic cancer, clinical screening of at-risk family members should begin at a younger age than is usual in the general population. "

" In addition, surgical management and adjuvant therapy may differ in patients with hereditary cancer, compared with those who have a sporadic cancer. Once a mutation has been identified in a family, genetic testing can determine which relatives are at increased cancer risk and are candidates for surgical intervention, chemoprevention, and additional screening. Family members who do not have the familial mutation can be reassured that they are not at increased risk of cancer but also can be advised that they should nonetheless participate in screening procedures recommended for the general population. "

" The overall goals of determining genetic risk are to prevent cancer if possible and to identify it at an earlier, more treatable stage. The following information reviews the role of genetic changes for specific cancers, with an emphasis on how to identify and manage at-risk relatives. "

" In the United States, the lifetime risk of breast cancer in women is 11%. Therefore, many patients have at least one relative with the disease. Most of these cases are classified as either sporadic or familial cancer, and lifetime risks for relatives can be estimated from statistical models. However, breast cancer is hereditary in about 7% of cases (2) and follows an autosomal dominant pattern of inheritance in affected families. Since hereditary breast cancer can be transmitted through either the mother or the father, it is important to review both maternal and paternal family histories when assessing each patient's cancer risk. "

" Most of the hereditary breast cancer syndromes identified to date are associated with increased risk for cancer in other organs as well (table 1). Therefore, when evaluating the significance of a family history of breast cancer, the clinician should collect information about all cancer in the family. Syndrome identification helps determine which cancer risk and which specific genes should be considered for testing. "

" Breast cancer, benign ovarian tumors, testicular tumors, pancreatic cancer, polyps of ureter, bladder, GI tract (often juvenile polyps), renal pelvis, bronchus, nasal passage. Melanin spots on lips, buccal mucosa, digits "

"Adapted from Online Mendelian Inheritance in Man (OMIM). Center for Medical Genetics, Johns Hopkins University, Baltimore, and National Center for Biotechnology Information, National Library of Medicine, Bethesda, 1999. Available at: "

". The risk of both breast and ovarian cancer is significantly elevated in patients who carry a mutation in "

" or both, but the risks vary among and within families. The reason for this variation is not completely understood, but it appears to be due to a complex interaction among environmental factors, modifying effects of other genes (epigenes), and the specific mutation itself. "

" mutations, breast cancer is more likely to develop at a young age and to be bilateral. The risk of ovarian cancer is also increased in these women. Men with "

" mutation are also at increased risk of breast cancer. Table 2 summarizes cancer risks in persons with "

" testing depends on the family history, which should include information about ancestry, age at breast cancer onset, its laterality, and associated cancers. Mutations in the "

" genes are rare in the general population, with an incidence estimated at 1 in 500 to 1 in 833 (7). Consequently, population screening is not advised. However, more than 90% of families with a history of hereditary breast and ovarian cancer ("

" mutations. The same is true for families with hereditary breast cancer in which one or more males are affected. In contrast, at least one third of families with hereditary, site-specific breast cancer ("

" mutation. Mutations in these genes are 10 times more common in persons of Ashkenazi Jewish descent. About 2% of this population carries one of three specific mutations (185delAG or 5382insC mutation in "

" genes do not account for all hereditary breast cancer, when possible, genetic testing should begin with an affected relative to determine if a mutation can be identified. If a mutation is found, testing other relatives distinguishes who is at increased cancer risk. In contrast, if a mutation is not identified in the family, an increased cancer risk cannot automatically be ruled out. The family may have mutation in a different gene or a "

" mutation that is not detectable with current testing methods. In these cases, cancer risk to relatives is determined through pedigree analysis and statistical risk models. "

" mutation have been established (table 3) (8), the effectiveness of these recommendations in reducing cancer morbidity and mortality is not certain. In particular, women should be counseled about the limitations of ovarian cancer screening. Prophylactic surgery (mastectomy or oophorectomy) is an option for reducing--but not eliminating--cancer risk. In addition, use of oral contraceptive drugs may reduce ovarian cancer risk in women who carry the "

" mutations by as much as 60% (9). The use of various estrogen inhibitors in reducing hereditary breast cancer risk is currently being investigated. Patients should be advised of the benefits, risks, and limitations of surgical and chemotherapeutic prevention methods. "

"Transvaginal ultrasound with Doppler color flow every 6-12 mo, beginning at age 25-35 yr "

" In the US population, the lifetime risk of colorectal cancer is about 6%. Consequently, many patients report a family history of colorectal malignancy. Most of these families share environmental risk factors (eg, high-fat, low-fiber diet, sedentary lifestyle) and polygenic or environmental risk factors that interact with one another. In contrast, predisposition to colon cancer is inherited as an autosomal dominant condition in a small percentage of families. The most common hereditary colon cancer syndromes are summarized in table 4. "

" Fewer than 100 colonic polyps, predominance of right-sided polyps, later onset of colorectal cancer with fewer than 40 polyps. May be increased risk of gastric and duodenal adenomas or cancer or both "

" Extracolonic manifestations: radiopaque lesions and osteomas of skull and mandible, congenital hypertrophy of pigment epithelium, dental abnormalities, epidermoid cysts, keloid scarring, lymphangiomas, lipomas, desmoids "

" Early-onset colorectal cancer, increased tendency of right-sided (proximal) colon cancer and multiple primary tumors. Extracolonic cancers: cancers of endometrium, ovary, small bowel, stomach, pancreas, ureter, renal pelvis "

" A clinically recognizable form of hereditary colon cancer is familial adenomatous polyposis (FAP). This disorder accounts for about 1% of all colon cancers. In the classic form, patients have hundreds of colon adenomas or polyps. Some also have specific types of tumors outside the colon. In classic FAP, 15% of at-risk patients have polyposis by age 10, 75% by age 20, and more than 90% by age 30. Without intervention, the risk that colorectal cancer will develop in a person with polyposis approaches 100% by age 50 (10). "

" An attentuated form of FAP presents with fewer than 100 polyps, tends to involve the proximal colon, and is associated with a later onset of colorectal cancer. In both forms, each son or daughter of an affected person has a 50% chance of inheriting the predisposition to polyps and cancer. "

" tumor suppressor gene. Genetic testing by protein truncation assay detects more than 80% of mutations that cause FAP (11). Patients with the disease should be tested for genetic mutations before unaffected relatives are screened. If a mutation is found, unaffected relatives then can be offered screening procedures to learn whether they are at risk for FAP. "

" Recommendations for the care of patients at risk for FAP include annual flexible sigmoidoscopy, beginning at age 10 or 11 years, and prophylactic colectomy once polyps are present (10). In some families, screening for tumors outside the colon may be indicated. Administration of the nonsteroidal anti-inflammatory drug sulindac (Clinoril) may reduce the number and size of polyps in patients with FAP (12). Additional research on the outcomes of chemoprevention is required before its long-term effectiveness is clear. In the future, such therapies may be an alternative to colectomy. "

" Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for 1% to 5% of all colon cancers. This condition is distinguishable from classic FAP because few or no polyps develop in at-risk patients and cancer is more likely to occur in the ascending colon. "

" Differentiating HNPCC from attenuated FAP can be difficult. HNPCC is associated with early-onset colorectal cancer, with an average age of diagnosis at about 44
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