Detecting and managing hereditary colorectal cancer syndromes in your practice
ABSTRACTHereditary syndromes account for 5% to 10% of cases of colorectal cancer. In clinical practice, patients with these syndromes need to be identified to ensure that they and their families receive genetic counseling and testing and appropriate risk-reducing treatment. Genetic testing can offer a precise diagnosis. It allows for risk stratification and focused management and surveillance.
KEY POINTS
- Hereditary colorectal cancer syndromes carry a substantial risk of intestinal and extraintestinal tumors.
- Affected patients need increased cancer surveillance and may benefit from prophylactic surgery.
- Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history.
- Patients suspected of having hereditary colorectal cancer syndromes should be referred for genetic counseling and, if appropriate, for genetic testing.
MYH-ASSOCIATED POLYPOSIS
Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.
Genetics of MYH-associated polyposis
MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.43 These two mutations are estimated to occur in 1% to 2% of the general population.44
Clinical presentation of MYH-associated polyposis
MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.48 Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.49 Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.49
Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.50,51
Diagnosis of MYH-associated polyposis
Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. 14 It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.52 The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.
Management of MYH-associated polyposis
The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.14 Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.49
GENETIC COUNSELING AND GENETIC TESTING
The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.16 They further recommend genetic counseling and informed consent before genetic testing.16
Genetic counseling is a process of working with patients and families whereby:
- A detailed medical and family history is obtained
- A formal risk assessment is performed
- Education about the disease in question and about genetic testing is provided
- Psychosocial concerns are assessed
- Informed consent is obtained when genetic testing is recommended.53
This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.
In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.54 In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.
When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.
Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.
Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.
