ABSTRACT: The Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), is the most common form of hereditary colorectal cancer (CRC), accounting for 2% to 7% of all CRC cases. The next most common hereditary CRC syndrome is familial adenomatous polyposis (FAP), which accounts for less than 1% of all CRC. Lynch syndrome is of crucial clinical importance due to the fact that it predicts the lifetime risk for CRC and a litany of extra-CRC cancers (of the endometrium, ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelial tract, and brain) through assessment of a well-orchestrated family history. A Lynch syndrome diagnosis is almost certain when a mutation in a mismatch repair gene—most commonly MSH2, MLH1, or, to a lesser degree, MSH6—is identified. Once diagnosed, the potential for significant reduction in cancer-related morbidity and mortality through highly targeted surveillance may be profound. Particularly important is colonoscopy initiated at an early age (ie, 25 years) and repeated annually due to accelerated carcinogenesis. In women, endometrial aspiration biopsy and transvaginal ultrasound are important given the extraordinarily high risk for endometrial and ovarian carcinoma. These cancer control strategies have a major impact on at-risk family members once they have been counseled and educated thoroughly about Lynch syndrome’s natural history and their own hereditary cancer risk.
Colorectal cancer (CRC) is the third most common cancer in the United States, where its annual incidence is estimated to be over 145,000. As the second highest cause of cancer death in the United States (surpassed only by lung cancer), its annual mortality is expected to exceed 56,200. Estimating that ~10% of the total CRC burden is hereditary, this incidence translates to close to 14,500 new cases with more than 5,620 deaths. These are conservative estimates, given the striking genotypic and phenotypic heterogeneity of hereditary CRC (Figure 1). In turn, its familial incidence-namely a two- to-threefold excess risk of CRC in patients who have one or more first-degree relatives with CRC but who do not fit any of the hereditary criteria-is estimated to be 15% to 20%, or 22,050 to 29,400 new cases and 8,505 to 11,340 deaths annually.
The remainder of CRC cases will be "sporadic," which implies that none of the patient's first- or second-degree relatives have been diagnosed with CRC. However, more meticulous probing of the family history among so-called sporadic or familial cases may identify a hereditary syndrome (Figure 1). In most hereditary CRC syndromes, certain extra-CRC cancer types may be integral lesions. Those that have been shown to be integral to the Lynch syndrome are listed in Table 1.
Physicians must understand how powerful the family history can be in determining a patient's risk for cancer. They also must know the natural history of the Lynch syndrome, in concert with the availability and significance of molecular genetic testing, so that this knowledge can be applied to effective genetic counseling, screening, and management.
Familial and Hereditary Cancer Risk
Public awareness of "familial" and "hereditary" cancer risk is increasing. Clinically, both physician and patient are concerned about the significance of "cancer risk." For example, firstdegree relatives of patients affected with common malignances such as carcinoma of the breast and colon, have approximately a twofold increased risk for cancer at the same anatomic site. Twin studies, particularly those showing higher concordance of cancer in monozygous twins than in dizygous twins, provide evidence to support this familial cancer risk, as in the case of carcinoma of the breast.
When searching for an explanation for familial or hereditary cancer risk, only about 20% of this twofold excess risk to relatives of affected breast cancer patients will be attributable to mutations in the BRCA1 and BRCA2 genes. The same phenomenon occurs in hereditary forms of CRC, as in the case of the Lynch syndrome and its MSH2 or MLH1 etiology.[7,8] In reviewing the familial occurrence of common cancers, Houlston and Peto suggest that its magnitude may be greater than currently appreciated in that the remaining familial risk could be due to mutations in as yet unidentified genes and/or to polygenic mechanisms, the latter being a more plausible explanation for familial cancer that does not follow a Mendelian inheritance pattern.
Hereditary CRC Syndromes
The two operationally defined categories of hereditary CRC are (1) tumors with chromosomal instability, which tend to be left-sided, show aneuploid DNA, harbor characteristic mutations such as K-ras, APC, and p53, and behave aggressively (eg, familial adenomatous polyposis [FAP]); and (2) tumors that show microsatellite instability, occur more frequently in the right colon, have diploid DNA, harbor characteristic mutations such as transforming growth beta type II receptor and BAX, and behave indolently (eg, Lynch syndrome).[7,8]
Logistics of Family Studies
Hereditary cancer syndromes can also be classified into two categories. The first includes disorders with phenotypic stigmata that can assist in establishing a hereditary cancer syndrome diagnosis. Striking examples include the multiple atypical nevi in the familial atypical multiple mole melanoma syndrome and the multiple colonic adenomas in FAP.
The second category includes disorders that lack such phenotypic stigmata of hereditary cancer risk. Classic examples in this category are the hereditary breast-ovarian cancer (HBOC) syndrome[12,13] and Lynch syndrome.[7,8] In these latter settings, particular reliance must be given to the cancer family history coupled with knowledge of the pattern of cancer distribution within the family-factors that are mandatory for hereditary cancer syndrome diagnosis.
Problems in interpreting the significance of the family history may arise. For example, the diagnosis of hereditary forms of cancer may be obfuscated by numerous factors, such as reduced penetrance of the deleterious mutations, genotypic and phenotypic heterogeneity, small families, false paternity, unavailability of medical and pathology records, slides, and/or tissue blocks, premature death of key relatives from causes other than cancer, lack of cooperation of otherwise informative relatives, and even decreased cooperation by their physicians.
In spite of the diagnostic and cancer- control virtues embodied in a wellorchestrated family cancer history, a severe failure in its collection and/ or accurate interpretation at the clinical level often exists. Confounding this omission, there may be a profound gap in knowledge between both clinical and basic science advances and their cancer-control translation at the bedside. Certain of those potential barriers may delay hereditary cancer syndrome diagnosis and management.
Once the pedigree is analyzed and shown to be consonant with Lynch syndrome, certain measures can enable confirmation of the diagnosis, such as the presence of microsatellite instability in a CRC specimen from a genetically informative relative and, if positive, a search for a cancer-causing germ-line mutation (MSH2, MLH1, MSH6). The identification of a cancer-causing mutation that cosegregates with the cancer phenotype then becomes the sine qua non for a hereditary cancer syndrome diagnosis. From this point on, the most important considerations will be predicated by the physician's knowledge of hereditary CRC, including its differential diagnosis in concert with the known extant phenotypic and genotypic heterogeneity of hereditary CRC syndromes (Figure 1). This information must then be coupled with knowledge of the cardinal features of hereditary cancer (Table 1), in concert with those myriad multifaceted problems that affect patient compliance and management.
Power of a Germ-line Mutation
The power of a cancer-causing mutation in a patient/family is truly enormous. This has been investigated in members of 75 HBOC and 47 hereditary nonpolyposis colorectal cancer (HNPCC) families. Collectively, this comprised 10,910 cohort members, of whom 1,408 were tested and learned about their results. Therein, carrier risk status changed in 2,906 patients following testing of 1,408 family members. The risk change to noncarrier status was most common, accounting for 77% of risk changes. Twelve percent changed to knowncarrier status from a lower risk. Sixty percent of persons with a carrier risk status change were not themselves tested, and yet their risk status changed because of a relative's test result.
Conclusions of the investigation were as follows: (1) Changes from uncertainty to certainty, ie, to carrier or noncarrier status, accounted for 89% of risk changes resulting from testing; (2) because most changes were risk reductions, economic and emotional burden lessened; and (3) research into the impact of testing on untested family members is clearly needed. Thus, this study had a major impact on the clinical, economic, and emotional implications of DNA testing in two of the most common hereditary cancer syndromes, namely HBOC and the Lynch syndrome.
Molecular Genetics and the Lynch Syndrome
Mutations in six different mismatch repair genes have been identified in HNPCC patients: MLH1, located on chromosome 3p21; MSH2 on 2p16; MSH6 on 2p15; PMS2 on 7p22; MLH3 on 14q24.3; and possibly PMS1, located on 7p22.[17-22] However, only 40% to 60% of Lynch syndrome patients harbor identifiable germ-line mutations.[23} Approximately 90% of the identified HNPCC mutations involve MLH1 or MSH2, whereas mutations in the MSH6 gene account for approximately 10%. MSH6 mutations appear to predispose to a milder form of Lynch syndrome and often show an excess of endometrial cancer.
These findings suggest that other genes, including modifier genes, may be of etiologic importance in Lynch syndrome. The occurrence of mutation types that are difficult to detect and/or yet to be identified as well as environmental factors and/or chance could also explain the etiology of those 40% to 60% of HNPCC families in which, to date, no known cancer-causative germ-line mutations have been identified.[7,26] The mutation database maintained by the International Collaborative Group (ICG)-HNPCC is an important source of first reference (www.nfdht.nl). Suter et al reported findings of a germ-line epimutation in two individuals who lacked evidence of germline mutations in any mismatch repair genes but who nevertheless met clinical criteria for the Lynch syndrome. These authors noted that the characteristics of epigenetic states could produce patterns of disease risk that resemble those attributed to polygenic mechanisms. In addition, it is hypothesized that rare germ-line mutations and polymorphisms of low penetrance, such as those that have been identified in FAP,[28-30] may have as yet unidentified counterparts in the Lynch syndrome.
We must bear in mind the absolute necessity of genetic counseling prior to DNA collection and testing, as well as at the time of disclosure of results, considering that the presence of a cancer- causing germ-line mutation will have a strong impact on the patient's lifetime destiny for cancer. Thus, this precious and potentially lifesaving knowledge will enable disclosure of risk for cancer(s) of specific anatomic sites, average age of onset, and possibly even prognostic differences in the patient bearing the specific cancercausing mutation. This knowledge will be limited only by the deleterious mutation's penetrance and the possible impact of environmental carcinogenic interaction.
To maximize the cancer control potential from a family study, the proband and his or her high-risk relatives should be notified about the hereditary cancer syndrome's natural history and the pertinent lifetime cancer risk. Genetic counseling must include an opportunity for DNA testing when this is appropriate; however, the candidates for testing must be made aware of its pros and cons. Surveillance and management opportunities for these high-risk relatives will then be highly targeted, based upon the natural history of the particular hereditary cancer disorder coupled with the presence of a cancer-causing germline mutation, when one is present. Counselees must be prepared psychologically and must have an opportunity to address freely such concerns as survivor guilt if found to be negative for the deleterious mutation, or, if positive, concerns about insurance and employment discrimination, and even the possibility of stereotyping by their relatives.
Family Information Session
Cancer-control objectives can be significantly abetted through a family information session. This involves the participation of as many family members as desire to assemble at an educational session, in a geographic area of convenience to the family. The family information session is conducted by a physician, a study coordinator (who may be a registered nurse), and a genetic counselor. Participants are educated in depth about the natural history of the particular hereditary cancer syndrome in their family, availability of genetic testing, and the surveillance and management options available to them. Blood draws for germ-line mutation testing, when indicated, will follow genetic counseling in consenting individuals.
The proband or a motivated family member can be extremely helpful in setting up the family information session in that they can notify their relatives of the upcoming family information session, assist in identifying an adequate facility for the session, and sign up family members for individual counseling appointments.
These family information sessions enable the physician and genetic counselor to discuss diagnostic and cancer control measures, as well as help to define confidentiality, psychosocial, and economic concerns that may have an impact on the family, and then determine how best to resolve them. A group psychosocial therapy situation often evolves. Family members frequently state that this was the first time a physician told them face-toface what could kill them and, in turn, what they could do about ameliorating the many diagnostic, screening, and management problems that they may encounter and/or may have already encountered as a result of being at increased hereditary cancer risk.