Vol. 17: Summer, 1999
Genetic Cancer Syndromes
Genetics of Colorectal Cancer
A Review for Primary Care Providers
Introduction
Colorectal cancer is the second leading cause of cancer deaths in the United States. An estimated 131,200 cases were diagnosed in 1997, representing about 9% of new cancer diagnoses. About 4-6% (or one in 25 to one in 17) of individuals in the United States will develop colorectal cancer, with approximate equal distribution between men and women. The average age of incidence is 67 years, with over 90% of deaths occurring in individuals over age 55. Incidence rates of colorectal cancer have declined in recent years, primarily as a result of increased screening and polyp removal, which inhibits progression of disease to invasive cancer.
Highly penetrant susceptibility syndromes inherited in an autosomal dominant pattern account for 3-7% of colon cancer cases. Another 15-20% show a less dramatic familial clustering, with the remainder considered 'sporadic' cancers. Although all colon cancers result from a series of somatic genetic mutations, those that are highly penetrant or familial are very likely the result of inherited mutations. The analysis of these mutations at the various stages of cancer or polyp development has allowed for a well-defined model for colorectal tumor development.
Occurrence of colorectal cancer in a first degree relative has been estimated to confer approximately a three-fold risk for this malignancy. At least one study demonstrated that the presence of adenomatous polyps in first degree relatives less than 60 years old also increases the risk three-fold. Although this information is useful for counseling, it presupposes knowledge of polyp information from the extended family members. In addition to genetic factors, pre-existing inflammatory bowel disease and a diet high in fat and low in fiber are recognized risk factors for colorectal cancer.
Obtaining a family history
Because the efficacy of early and regular screening for individuals at increased risk for developing colon cancer is well documented, it is important to identify high risk individuals. However, providing recommendations for medical management requires that a detailed and accurate medical/family history be obtained. Challenges to this task include the lack of knowledge many people have about health history of family members, especially concerning information from screening tests such as sigmoidoscopy or colonoscopy.
However, as outlined elsewhere in this newsletter, a complete family history includes identifying all the relatives (both maternal and paternal) from three generations with neoplasia. This usually comprises parents, siblings, children, grandparents, aunts, uncles, nieces, nephews and cousins. For each of these individuals, information about any primary cancer diagnosis is important (site, age of onset, stage). Information about colon screening (was it done, what were the results) is important to document.
Many of these reported cancers and polyps will require medical record confirmation to assure that the most useful risk assessment is provided to the patient. Family and personal history of polyps is especially important to confirm due to the various types of polyps and their associated risks. Clues that the cancer may have an inherited component will include a young age of onset of cancers and several family members with polyps or colon cancer.
Common colon cancer syndromes
Familial colorectal cancers can be divided into two groups: those characterized by the presence of multiple benign colorectal polyps (polyposis); and those characterized by the absence of polyps. The two best understood diseases are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC).
FAP is an autosomal dominant inherited disease due to mutations in the APC gene in chromosome 5. Affected individuals develop hundreds to thousands of adenomatous polyps during the second and third decades of life. These polyps resemble the sporadic adenomatous polyps that develop in the general population. Although an individual FAP polyp is no more likely to progress to cancer than is a sporadic polyp, their large numbers make it more likely that some will progress to cancer. The median age for colorectal cancer in patients with FAP is about 40. Thus, prophylactic colectomies are routinely performed on FAP patients to reduce their risk of developing cancer.
Although one in 5000 individuals are affected with FAP in the United States, fewer than 1% of all colon cancer cases occur in patients with FAP, in part due to prophylactic colectomy. Patients with FAP are also at increased risk for cancers of the thyroid, small intestine, stomach and brain. FAP variants (e.g., Gardner syndrome) include extracolonic manifestations, such as soft tissue tumors, osteomas, and dental abnormalities. Gardner syndrome, like FAP, is due to mutation of the APC gene. Approximately 25% of people with FAP represent individuals who have a new mutation, so not all patients with FAP have a family history of polyps or cancer.
HNPCC accounts for about 2 to 4% of colorectal cancers. The median age of disease onset is 40 years. These patients lack a marked increase in the number of precursor adenomas. Until recently, HNPCC kindreds had to be defined by pedigree analysis, with at least three first degree relatives in at least two different generations coupled with early onset colorectal cancer (less than 50 years old) in at least one affected family member. About 70% of families which meet this criteria have recognizable mutations.
The majority of HNPCC patients inherit defects in the DNA mismatch repair genes, causing DNA to be genetically unstable and allowing rapid progression to cancer. Individuals who have inherited mutations in the HNPCC mismatch repair genes are at risk for cancers other than those of the colon. Other cancers seen in HNPCC families include those of the urinary tract, ovary, stomach, and uterus.
Knowledge of mutation status in FAP and HNPCC families allows for presymptomatic diagnosis in members of those families. Individuals with that knowledge can increase surveillance or be reassured to a risk equal to that of the general population.
Less common colon cancer syndromes
In addition to FAP and HNPCC, there are a number of rarer syndromes with colon cancer. The identification of families, genetic testing options, screening and medical management differ for each. Appropriate referrals to a cancer genetic center to clarify the syndrome for the patient, as well as his or her family, are important.
Turcot syndrome is an autosomal dominant condition in which the number of polyps ranges from 5-10 to over 100. In addition to colorectal cancers, brain tumors are also seen in individuals who have disease-causing mutations. Since the age of onset can be in the teens, screening recommendations include baseline flexible sigmoidoscopy from age 10. Because brain gliomas are seen at young ages, screening CT scans and MRIs are also recommended.
Peutz-Jeghers syndrome is also an autosomal dominant condition which involves polyps in the stomach, small bowel and colon. In addition to those sites, cancer can develop in the testes or ovaries. A characteristic feature of this condition is the melanin spots seen on the lips, buccal mucosa, face, forearms, and digits. The average age of diagnosis is the mid-20s and no known mutation has been identified in these families.
Muir-Torre syndrome is considered an HNPCC variant and includes sebaceous skin lesions that typically present in the fourth decade and a broad range of internal malignancies, such as stomach, endometrium, kidney, ovaries, and bladder.
Familial juvenile polyposis, as the name indicates, involves juvenile polyps that can occur in the first decade of life. Most of the polyps are found in the colon, but some can be seen in the stomach and small bowel. About a third of the cases are familial, but the genetic and environmental factors involved are not yet known. The risk of cancer in these patients is 10-25% and screening recommendations are case specific.
Cowden disease is a rare condition that involves multiple hamartomatous polyps of the skin and mucous membranes. About one third of affected patients demonstrate polyps, although many are often not screened, since there does not appear to be an increased risk of developing colon cancer. It is an autosomal dominant condition, but penetrance is unclear because an asymptomatic skin papule is the most common manifestation and is often unrecognized. However, thyroid cancers have been seen and women are at an increased risk for breast cancer. Therefore, confirming the diagnosis and developing a screening regimen is important.
Familial colon cancers
The vast majority of colon cancer cases are considered sporadic, but many studies have demonstrated that first degree relatives of affected individuals have about a three-fold increased risk of developing colon cancer. In addition to sharing potentially inherited susceptibility mutations, these families often share similar environmental factors, such as geographical location and diet. Screening for first degree relatives of individuals with colorectal cancer should include an annual fecal occult blood analysis and sigmoidoscopy every three to five years. The age to begin screening is partially dependent upon the age of onset of the cancers in the family.
Predictive testing for colon cancer
The first step to offering predictive testing for colon cancer is to identify families that would likely have a mutation and developing a testing strategy for each family. The most appropriate person to be offered testing is a family member who has had cancer, often a member of the oldest generation. If a mutation exists in a family, it is more likely to be present in a person who has cancer. Testing the oldest generation first prevents a parent from learning about his or her genetic status as a result of information available from a child and honors the ability of the parent to make a voluntary, informed choice about personal testing. Once a mutation has been identified, the elements of informed consent for genetic testing (which are detailed in the breast cancer section of this document) should be met prior to obtaining blood on extended family members. These elements include a discussion of the risks, benefits and limitations, as well as the medical management options for people who have an identifiable mutation as well as those who do not.
There are several key differences between predictive testing for colon cancer and breast cancer, including the efficacy of colon screening, which is higher than that for breast screening. In addition, since several of the colon cancer syndromes impact children, the rationale for testing minors in much stronger with regard to predictive testing for some colon cancer syndromes. Children who do not have the mutation seen in other family members benefit by not undergoing the invasive colon screening.
Summary
There are many recognizable inherited syndromes that involve colon cancer. Hence, it is valuable for the primary care provider to obtain a family history from individuals who are diagnosed with colon cancer. Clues that the cancer may have an inherited component include a young age of onset and other family members with polyps or colon cancer. For those families who meet appropriate criteria, referrals for genetic counseling and testing may help provide information about the cause of the cancer in the affected individual and allow for predictive testing for other family members. While assessment of risk for the extended family members and genetic testing can be complex (and best provided by cancer risk specialists), general information about colon cancer and screening should be offered by primary care providers.
Contributed by Vickie L. Venne, MS (UT)
References:
Biesecker BB, Garber JE (1995): Testing and counseling adults for heritable cancer risk. JNCI Monograph 17: 115-118.
Boland CR, Thibodeau SN, Hamilton SR, et al (1998): A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58: 5248-57.
Burt RW, DiSario JA, Cannon-Albright L (1995): Genetics of colon cancer: impact of inheritance on colon cancer risk. Ann Rev Med 46:371-379.
De la Chapelle A, Peltomaki P (1995): Genetics of hereditary colon cancer. Ann Rev Genet 29: 329-348.
Rossi SC, Srivastava S (1996): National Cancer Institute Workshop on Genetic Screening for Colorectal Cancer. JNCI 88:331-339.
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
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