How does family history impact risk assessment for cancer?

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Individuals who have a familial risk of developing cancer are those who also have with a strong family history of cancer, including affected relatives with unusual or multiple cancers or family members diagnosed at atypically early ages. Although having a family history can increase one’s risk of cancer, it does not necessarily mean that one will go on to develop cancer.
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Inheritance patterns and incidence of cancer in family members: In any discussion of family risk for cancer, it is important to note that individuals can inherit an increased risk of developing cancer, but they do not inherit the disease itself. In fact, a known risk of developing cancer can actually reduce a family member’s susceptibility to cancer by encouraging that individual to adopt healthy behaviors, such as regular medical checkups, good eating and exercise habits, and, for some, prophylactic treatments. Although some individuals may be aware of a family history of cancer, others must be identified by the prudent physician or other health care professional so that they may be appropriately referred for genetic counseling and testing.

Cancers have different inheritance patterns, and the risk of a family member who has an affected first-order relative may vary with the type of cancer. For example, research indicates that pancreatic cancer is currently considered attributable to a genetic mutation (an event that changes the genetic structure or genotype of an individual or organism). The majority of genetic mutations that lead to cancer occur in genes that control growth through exposure to carcinogens or errors made by cells when they divide or replicate. Research has shown that patients with hereditary pancreatitis (not to be confused with chronic pancreatitis of common etiology) have a 40 percent increased risk of developing pancreatic cancer. Most research indicates that pancreatic cancer risk involves patients with a paternal inheritance pattern of disease (hereditary pancreatitis), while some research reports evidence of a maternal inheritance pattern. In addition, mutations of BRCA1, a gene known to suppress tumors, have been associated with increased risk of developing pancreatic cancer, as well as breast cancer and fallopian tube cancer.

Breast cancer is not inherited; rather, it is caused by somatic (environmental) mutations in breast cells during one’s life. BRCA2, another gene known to suppress tumors, has been linked with an increased risk of breast cancer, as well as with prostate and pancreatic cancers in men. A higher incidence of the skin cancer melanoma is also more common in individuals with BRCA2 mutations than those without.

In addition to BRCA1 and BRCA2 genes, variations of which have been linked to some forms of breast cancer, presence of the following genes in an individual increases the risk of breast cancer by causing syndromes that also increase the risk of developing other types of cancer: CDH1, PTEN, STK11, and TP53. The presence of variations in the following genes has also been associated with breast cancer: AR, ATM, BARD1, BRIP1, CHEK2, DIRAS3, ERBB2, NBN, PALB2, RAD50, and RAD51. Although not all the evidence implicates variations in these genes as risk factors for developing breast cancer, the evidence is strongest for ATM and CHEK2. An accumulation of genetic mutations in genes responsible for cell growth, cell division, or repairing deoxyribonucleic acid (DNA) promotes cancer-cell proliferation resulting in tumor growth. Inherited patterns or cancer syndromes that increase risk of breast and ovarian cancer include breast-ovarian cancer syndrome, nonpolyposis colorectal cancer syndrome, Cowden syndrome, Peutz-Jegher syndrome, and Li-Fraumeni syndrome, and inherited mutations that increase the risk for other types of cancers.

Some cancers follow established hereditary patterns such as autosomal dominant inheritance. An autosomal dominant inheritance pattern consists of one mutated copy of the particular gene in each cell transmitted by one affected parent, occurring in every generation of an affected family. The pedigree of a family affected by a hereditary cancer syndrome will indicate whether that cancer has been inherited as an autosomal dominant disorder in which case as many as half of the offspring of each carrier may develop a cancer related to the inherited syndrome. Two cancers that follow this pattern are a hereditary form of breast-ovarian cancer syndrome and Lynch cancer family syndrome, which is characterized by increased incidence of cancer of the right colon and increased incidence of endometrial cancer and multiple primary malignant neoplasms. Another type of autosomal dominant hereditary pattern, hereditary nonpolyposis, is responsible for between 2 and 7 percent of all cases of colorectal cancer. Mutations in the genes (including MLH1, MSH2, MSH6, and PMS2) that are responsible for repairing errors made when cells are copied can lead to uncontrolled cell growth and possibly cancer. This condition also increases an individual’s risk for cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, skin, brain, and prostate. Women who inherit this disorder are at greater risk for endometrial and ovarian cancers.

Several hereditary cancer syndromes have been identified for which there are effective diagnostic tests and options for managing the disease, including those for cancers of the breast, ovary, colon, and endometrium, to name a few. These hereditary syndromes include hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome); familial adenomatous polyposis (FAP), an inherited colorectal cancer syndrome; hereditary breast and ovarian cancer (HBOC); and multiple endocrine neoplasia 2 (MEN 2) in conjunction with parathyroid hyperplasia, which has been linked to thyroid cancer. Individuals genetically tested and found to have any of these syndromes can discuss specific options for managing their susceptibility for cancer with a genetic counselor.

Genetic screening and testing: Routine screening for most cancers in the general population is neither recommended nor effective in reducing mortality from cancer. Moreover, because incidence of cancer varies in mutation carriers by type of cancer, screening and genetic testing must be approached by the type of inherited cancer and its risk patterns. For example, only 10 to 15 percent of breast cancer cases are thought to be familial, with about one-third caused by an inherited genetic mutation in a BRCA1 or BRCA2 gene. Over a woman’s lifetime, the incidence of breast cancer in a mutation carrier may be more than 50 percent, and an inherited BRCA1 mutation is also associated with increased risk of ovarian cancer. It is therefore recommended that only affected relatives with a family history of an inherited gene mutation BRCA1 or BRCA2 be screened. It should be noted that estimates of how many women with an altered gene will develop breast cancer range from 36 to 85 percent, and estimates of how many women with one of these altered genes will develop ovarian cancer range from 16 to 60 percent. According to a report published in GeneReviews in 2013, individuals with a mutation in BRCA1 or BRCA2 had a 40 to 80 percent lifetime risk for breast cancer and a 11 to 40 percent lifetime risk for ovarian cancer. Most research related to BRCA1 and BRCA2 has been done with large families and many affected individuals. Some of the incidence in these affected individuals may be due to other genetic as well as environmental factors; thus, risk estimates may not accurately reflect the risk in the general population of women, or in any individual woman. It must be emphasized, therefore, that genetic screening and testing is primarily for individuals to ascertain their inherited risk of developing cancer. Genetic testing can be used to determine who can benefit from regular, comprehensive cancer screenings, procedures to reduce the risk of acquiring the cancer, lifestyle and behavioral changes, medication, or prophylactic surgery.

Genetic counseling: For those individuals who do have a significant inherited risk for cancer, the health professional performing genetic counseling will ask the client to gather a family medical history and map a pedigree or family tree to illustrate the family history of the cancer. A variety of health professionals may perform genetic counseling and testing, including genetic counselors, nurses with advanced training and practice, psychologists, social workers, and physicians.

The client begins the family-risk-assessment process by talking to relatives, obtaining medical records of relatives, and noting any medical conditions that have occurred in the family and at what ages. It is recommended that the client chart a separate tree for each side of the family, maternal and paternal, recording the country of birth and ethnicity as well. For example, certain breast cancer genes have been associated with eastern European Ashkenazi descent. The National Society of Genetic Counselors (NSGC) recommends initially talking to first-order relatives (parents and siblings), then contacting second-order relatives going back one generation at a time, collating birth, marriage, and death certificates to form the chart or family tree and document a pedigree. A genetic counselor will often prefer a pedigree with three generations of family history. Some of the facts to include in constructing a pedigree are the name of each relative, age at death and cause of death if deceased, medical conditions and ages when these conditions were acquired, birth defects, fertility problems, learning challenges, and lifestyle patterns (exercise, smoking, drinking, addictions, obesity, and so on). Gathering information on lifestyle behaviors of affected family members is critical; apart from genes, families share lifestyles and environments that may contribute to increased risk of cancer and other disease conditions by altering genes. All this information is useful to the client personally, and it can also help identify inheritance patterns of disorders that may place offspring at risk.

After constructing the pedigree, the client will submit it to the counselor, who will thoroughly review the client’s personal, medical, and family history and evaluate the results. The client will meet with the counselor to hear the evaluation, discuss how the results relate to individual risk, and develop a personal prevention program. For example, the counselor will discuss hereditary cancer syndromes and what to look for to see if any syndromes are also present in family members.

If the results of the pedigree indicate the utility of genetic testing and the client wishes to go forward, the client will be asked to complete an informed consent form. The form will describe the benefits and limitations of testing for genetic susceptibility, as well as the particular policies and financial procedures associated with the site where the testing will be performed. There are myriad tests for various hereditary cancers; DNA sequencing is the most sensitive and reliable method used to test for a hereditary cancer syndrome. Once the lab informs the physician of the test results, the client will meet with the health professional performing the counseling for disclosure of the test results. These results will be discussed within the context of the family’s history so that risks can be communicated effectively. The counselor will also advise the client on any need to notify family members of a hereditary genetic mutation associated with an elevated risk for cancer. This is the time for the client to discuss perceived and real risks of cancer, emotional issues surrounding cancer, support systems, coping skills, and decision making.

Pros and cons of genetic testing: Most cancer is not due to the inheritance of a single genetic mutation. Sporadic cancers—those not due to a known, specific hereditary pattern—comprise 90 percent of all cancers diagnosed. Nevertheless, those with a hereditary inheritance pattern of a cancer are better positioned to adopt risk-reducing behaviors if they know they are at higher risk for certain types of cancer than others in the general population. Moreover, individuals who learn of their risk and begin risk-reduction behaviors at an early age may be able to reduce the risk of passing the mutation to offspring.

There are tremendous psychological effects and social costs for an individual who learns of his or her hereditary risk of developing cancer. A risk of family cancer can alter one’s lifestyle, inform family planning, or encourage family members to be tested. Those who are found not to have a hereditary risk may be relieved but may nonetheless be motivated to make healthy lifestyle changes. Specific interventions and potentially life-saving management options are available to individuals found to be at elevated risk of cancer following a genetic screening test. Some of these options include tamoxifen, a chemotherapy medication for breast cancer; colonoscopy to detect early colon cancer; and removal of ovaries and fallopian tubes. Some studies have found that prophylactic hysterectomy with bilateral salpingo-oophrectomy (removal of the ovaries and fallopian tubes) is an effective strategy for preventing endometrial and ovarian cancer in women with Lynch syndrome. According to the American Society for Clinical Oncology (ASCO) in 2014, premenopausal women with a BRCA genetic mutation who have had their ovaries removed reduce their risk of breast cancer by 50 percent or more. Studies have shown that women at increased risk of breast cancer due to BRCA2 mutations are less likely to develop the cancer if they take tamoxifen, a treatment for advanced breast cancer, for five years; according to the ASCO in 2014, doing so can reduce the risk of breast cancer by 50 percent. For those at greatest risk of developing breast cancer, prophylactic bilateral mastectomy has been shown to greatly reduce (but not eliminate) the risk of developing breast cancer; according to the ASCO in 2014, the surgery can reduce the risk by more than 90 percent.

While genetic tests for cancer risk provide valuable information to the patient and the physician, they are also fraught with controversy. Genetic tests may show increased risk, but they cannot determine degrees of risk or what actual risk an individual will have of developing cancer. A physician must evaluate the benefits and limitations of information on familial risk when deciding who to refer for genetic counseling and testing. The American Cancer Society and other organizations publish guidelines available online; these identify current clinical recommendations, promulgated by the US Department of Health and Human Services, for who should be screened and tested for different types of cancers.

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