Hereditary cancer predisposition syndromes account for a small percentage of all cancer diagnoses. Approximately 5% to 10% of all colorectal cancers are hereditary. The most prevalent hereditary colorectal cancer syndrome is Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC is caused by an inherited mutation in a DNA mismatch repair gene. Persons with Lynch syndrome have an increased lifetime risk not only for colorectal cancer, but also for endometrial, stomach, ovarian, urinary tract, and other cancers. Fortunately, established risk-management recommendations for patients with Lynch syndrome are associated with a decrease in cancer-related deaths.1
The first step in identifying a person at risk for Lynch syndrome is to obtain an accurate cancer history. Oncology nurses are essential in this step as they often have a close, ongoing relationship with their patients. Knowing the features of hereditary cancer syndromes can help save patients’ and their family members’ lives. This article provides a review of the current knowledge about Lynch syndrome, an overview of high-risk patient management, and strategies for identifying patients who are candidates for genetic evaluation.
MISMATCH REPAIR GENES
Inherited mutations occurring in any of four DNA mismatch repair genes—MLH1, MSH2, MSH6, or PMS2—have known associations with Lynch syndrome. Mutations in MLH1 and MSH2 cause approximately 71% of Lynch syndrome cases; mutations in MSH6 and PMS2 occur less often.2 Recently, a deletion in the gene TACSTD1 was found in families suspicious for Lynch syndrome and accounts for a small fraction of persons without an identifiable mutation in the four known mismatch repair genes.3
Mismatch repair genes are necessary for fixing incorrect pairings of nucleotide bases in DNA during the replication or copying process. If the error or “mismatch” is not corrected, the risk of the cell becoming cancerous is increased. All cells, except gonadal cells, have two copies of each mismatch repair gene. Persons with Lynch syndrome are born with one functional copy and one nonfunctional copy due to an inherited mutation. A tumor can develop when a person acquires a mutation to the one functional copy or allele.4 Thus, Lynch syndrome is inherited in an autosomal dominant manner, which means that a child whose parent has Lynch syndrome has a 50% chance of inheriting the mutation.
Persons with Lynch syndrome are at high risk for colorectal cancer as well as other cancers, most notably endometrial cancer. Lynch syndrome-related cancers often develop in multiple generations of a family, and these patients are usually younger at diagnosis than patients in the general population. The lifetime risk (up to age 70 years) for colorectal cancer is approximately 54% to 70% for men5,6 and approximately 42% to 52% for women,5,7 and average age of onset is 44 to 61 years.5 Comparatively, the lifetime risk for colorectal cancer in the general population is only about 5%, and median age of onset is 70 years.8
Those with Lynch syndrome are also more likely to develop a second primary colorectal cancer, which could occur simultaneously or at a later time. The cumulative risk per year after diagnosis for a second primary colorectal cancer is 3%; therefore, the risk for a second colorectal cancer within 10 years is 30%.9
For women with Lynch syndrome, lifetime risk for endometrial cancer is up to 60%, and median age of onset is 47 to 62 years.5,7,10 Conversely, the lifetime risk for endometrial cancer in the general population is approximately 2.5%, and median age of onset is 62 years.8 Women with Lynch syndrome also have a lifetime risk for ovarian cancer of up to 12% compared with less than 2% in the general population.10
Risk for gastric cancer is higher in persons with Lynch syndrome; their lifetime risk is 6% to 13%.10,11 In addition, risk for several other cancers, such as small bowel, hepatobiliary tract, pancreatic, renal pelvis, ureter, and brain, is higher in patients with Lynch syndrome than in the general population. Lifetime risk of each of these cancers is less than 10%.10,12
Because the majority of mutations are identified in MLH1 and MSH2, the risk estimates discussed above are more closely related to mutations in these two genes. Persons with MSH6 or PMS2 mutations have different colorectal and endometrial cancer risks. For example, colorectal cancer risk ranges from 22% to 69% among men with MSH6 mutations, whereas the risk for women is only 10% to 30%.13,14 An MSH6 mutation confers a lifetime risk for endometrial cancer of up to 71%; therefore, endometrial cancer develops more frequently in families with MSH6 gene mutations.13,14 Cancer risks in persons with a PMS2 mutation are not as clear, as mutations in this gene are seen rarely. One recent study estimated lifetime risks in PMS2-mutation carriers of only 15% to 20% for colorectal cancer and 15% for endometrial cancer.15 Other extracolonic cancer risks were also increased in persons with MSH6 and PMS2 mutations.13,15
CHARACTERISTICS OF COLORECTAL DISEASE
Colonoscopy screening can help differentiate Lynch syndrome from other hereditary colorectal cancer syndromes. Lynch syndrome is typically associated with fewer than 10 adenomatous (precancerous) polyps cumulatively, whereas familial adenomatous polyposis (FAP), also a hereditary colorectal cancer syndrome, is associated with hundreds to thousands of adenomas.22 In Lynch syndrome, adenomas are commonly seen in patients younger than 40 years, are frequently found to have a villous growth pattern with moderate- to high-grade dysplasia, and tend to develop into cancer more rapidly than in the general population.16 Both adenomas and tumors in the colon associated with Lynch syndrome occur most frequently on the right side of the colon, which is not examined with flexible sigmoidoscope.12 Tumors often have characteristic pathologic features such as poorly differentiated medullary-type features, mucinous features, signet-ring cells, a Crohnlike lymphocytic reaction, and infiltrating T-lymphocytes.17
IDENTIFYING FAMILIES WITH LYNCH SYNDROME
Assessment for Lynch syndrome begins with a thorough family cancer history that includes at least three generations of both maternal and paternal first-, second-, and third-degree relatives (Figure 1). All cancers in the family should be noted with the person’s age at diagnosis. Research criteria were developed to identify persons at risk for Lynch syndrome (Table 1). The original Amsterdam Criteria are limiting in that they accounted only for colorectal cancers;18 thus, a subsequent modification, Amsterdam Criteria II (AC II), includes extracolonic tumors.19 For those patients who meet AC II criteria, genetic testing of the four mismatch repair genes associated with Lynch syndrome can be offered.
A broader set of criteria, the Revised Bethesda Guidelines, was developed to determine when tumors should be screened for evidence of a mismatch repair defect21 (Table 1). Two commonly used screening tests for Lynch syndrome are microsatellite instability (MSI) analysis and immunohistochemistry (IHC) analysis. Because Lynch syndrome tumors often have loss of a mismatch repair protein due to mutations in the corresponding mismatch repair gene, the absence of protein can be detected through IHC analysis. Tumors caused by mutations in mismatch repair genes are frequently MSI high (MSI-H), which is an increased level of instability in tumor DNA; however, not all MSI-H colorectal tumors are due to Lynch syndrome. Ten percent to 20% of sporadic colorectal cancers are also MSI high.20 Patients with MSI-H tumors can be offered additional tumor screening, including IHC analysis or direct testing of the genes related to Lynch syndrome. One benefit of IHC analysis is that it can define which specific mismatch repair gene may be mutated, thus decreasing total test time and cost.
Patients who meet the revised Bethesda criteria should be referred for further genetic evaluation, especially those patients with a personal history of colorectal cancer at younger than 50 years or who have had another Lynch syndrome-related cancer such as endometrial, ovarian, stomach, urinary tract, or pancreatic cancer. Other patients with a personal history of a Lynch syndrome-related cancer at any age and a family history of colorectal cancer, adenomatous polyps, or a Lynch syndrome-related cancer in at least two first- or second-degree relatives should also consider genetic evaluation. Important limitations in family histories to consider are early death, adoption, lack of cancer screening, and small family size. When in doubt, or if the patient expresses a concern for hereditary cancer, refer the patient for genetic counseling.