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Genetic Counseling in Hereditary Nonpolyposis Colorectal Cancer

Genetic Counseling in Hereditary Nonpolyposis Colorectal Cancer

Menko and colleagues review the genetic counseling that occurs after the presymptomatic diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) is made. The discovery of the mechanism by which tumors develop in this setting and the cloning of the genes responsible for the disease have made possible the DNA-based diagnosis of a disease, which, less than 5 years ago, was a controversial entity. In a remarkably short period, the nature of HNPCC has been greatly elucidated, its relationship to defective DNA mismatch repair has become manifest, and the means to diagnose it in a presymptomatic state has been developed [1].

The first generation of diagnostic tests are now available, (Luce, et al, 1995) and no doubt, more sensitive and specific tests are on the way. Before long, diagnostic tests will become commercially available, and we will have to grapple with a number of possibly unforeseen issues. Physicians will be in a position to inform healthy adults with no premorbid phenotype that they are at extraordinary risk of developing cancer during their lifetime, and that this will tend to occur two to three decades earlier than the rest of the population. Although physicians have been counseling patients about their risk of neoplasia for many decades, they may be armed with a degree of certainty that was never previously possible. Will we be ready for this?

An Important Step Forward, But...

The presymptomatic diagnosis of certain diseases, eg, Huntington's disease, poses a formidable challenge, in that no effective therapy is available to prevent their morbid and lethal consequences. In the case of HNPCC, on the other hand, effective intervention is available that can dramatically reduce its adverse consequences. Accurate diagnosis within high-risk families can relieve some individuals of the need for lifelong diagnostic tests, including frequent colonoscopy, and can help convince affected individuals to accept proper management even when they are feeling well.

DNA-based diagnosis should, therefore, be considered an important step forward in the management of familial colon cancer. Certainly, there will be great enthusiasm to include these new approaches in our diagnostic armamentarium. However, we should consider the possibility that risks may accompany the ability to make this diagnosis. Can such knowledge have side effects?

The paper by Menko et al makes a number of important points. First, the diagnosis of HNPCC can now be made in smaller families in which the Amsterdam criteria would not likely be met. New mutations can be diagnosed and interpreted properly. In such instances, HNPCC has important implications for an individual and his or her offspring, but the risk does not extend to siblings or parents. Once a genetic diagnosis is confidently made, colonoscopic screening and appropriate gynecologic screening may be initiated, as outlined in the authors' Table 5. Moreover, psychological intervention and support may be started in the presymptomatic period, permitting the affected individual to deal with risk and familial issues independently of problems associated with personal health risks. This information will surely empower the properly informed patient with the means to reduce the risks of developing metastatic cancer.

Complexities of DNA-Based Diagnosis May Not Be Readily Apparent

However, the ability to make DNA-based diagnoses is fraught with complexities that may not be immediately apparent to the primary-care physician, surgeon, gastroenterologist, or oncologist. Numerous ambiguities may cloud the interpretation of a genetic diagnosis. Each of the different genetic approaches to the diagnosis of HNPCC has its own inherent strengths and liabilities, as the authors indicate. Every approach can miss the offending mutation, which results in a false-negative diagnosis.

Also, it is likely that we have not yet uncovered all of the genes that can produce HNPCC. The DNA mismatch repair system requires many proteins, of which four have been linked to HNPCC and several others have not. Furthermore, at least one of these genes (hPMS-1) has been linked to only one HNPCC family, and due to the nature of this mutation, it is possible that it does not actually cause the HNPCC. On the other side of the equation, it would appear that other members of the DNA mismatch repair system should be capable of causing HNPCC, but no families have yet been discovered with germ-line mutations in these genes. It will take time to establish with certainty all of the genes that may result in HNPCC.

Some diagnostic approaches will always miss certain classes of mutations. For example, direct sequencing of genes (the most rigorous but labor-intensive approach to the diagnosis), will miss mutations that affect gene expression, may miss alterations at intron-exon borders that can adversely affect splicing, and will miss large genetic deletions. Screening techniques, such as DGGE and SSCP, are intrinsically less sensitive than direct sequencing and are more likely to result in underdiagnosis. The protein truncation test (also called in vitro transcription/translation, or IVTT) detects only mutations that result in the translation of a pathologically foreshortened protein that is missing its carboxy-terminus [2].

False-Positive Diagnoses Also a Risk

False-positive diagnoses are an equal risk. As mentioned above, direct sequencing is likely to be the most sensitive approach for the detection of germ-line mutations in the DNA repair genes. However, interpretation of the sequences may not be simple. For example, certain variations in DNA sequence will be silent and not result in any change in the protein structure. Oth er variations may change the amino acid sequence of the protein (ie, a missense mutation), but this alteration may be "conservative" and not seriously affect its function. Therefore, the more sensitive direct-sequencing approach may detect a "polymorphism" that represents a deviation from the most common human sequences but still may not cause disease.

Investigators familiar with DNA sequencing and molecular biology may recognize these sequence variations as polymorphisms, but this may not be obvious to the uninitiated. Worse yet, mutations may come in a variety of "strengths," some of which are more powerful than others and may cause a more severe phenotype. The game is still young, and we are still in the process of trying to understand the implications of different types of mutations. If clinicians unfamiliar with the principles of molecular biology can obtain test results without assistance, errors can be made, and improper counseling may be offered.

The authors also raise the issue of indirect gene tracking, such as linkage analysis or other techniques that study the segregation of DNA polymorphisms linked to a disease-causing gene in a family. This approach may be potentially hazardous as well, depending on the propinquity of the marker locus to the disease-causing gene. This approach is usually used when a gene has been mapped but has not yet been cloned. Linkage analysis should be used with some caution.

HNPCC More Complicated Than Initially Thought

The more we learn about HNPCC, the clearer it becomes that the disease is more complex than initially thought. It was traditionally assumed that every gene carrier would develop cancer at an early age. It now appears that variable penetrance occurs in this disease. Skipped generations may occur [3,4], and some individuals may develop cancer later in life, without any explanation [4]. Examples have now been reported in which HNPCC was diagnosed in a parent after it had been diagnosed in his or her child [5]. Moreover, Liu et al [6] found HNPCC in several individuals who were selected for study after the exclusion of a family history of HNPCC.

It is not known whether the variable penetrance is related to different "strengths" of the germ-line mutation, the influence of environmental factors, or even the modulating influence of another gene, as appears to be the case in familial adenomatous polyposis [7]. We must be prepared for the accumulation of perplexing details about this disease.

Management Still in Evolution

The management of patients with a DNA-based diagnosis of HNPCC is still in evolution. Interestingly, Menko et al suggest that colonoscopy should be carried out every 2 to 3 years in "at-risk" individuals, as opposed to every 1 to 2 years in known gene carriers. The authors are attempting to cope with the utilization of resources for patients who are at 50% risk of the disease (ie, asymptomatic offspring of HNPCC patients for whom a genetic diagnosis has not been possible) vs a more intense regimen than those who are known to have HNPCC. Is this entirely rational? If 1- to 2-year colonoscopic intervals are appropriate for patients known to carry a gene for HNPCC, perhaps this approach should be used in patients at 50% risk until the diagnosis can be definitively excluded.

It will be very difficult to exclude the diagnosis of HNPCC until the affected gene is identified in a family. Thus, knowing more about the disease, but being unable to definitively rule it out in some patients, may increase the physician's anxieties about the disease and actually increase the use of preventive measures in such families. Finally, the authors stop short of recommending the most ambitious form of management, prophylactic colectomy (or perhaps subtotal colectomy). Although surgery would surely be rejected by many patients, others may prefer a surgical approach to a lifetime of colonoscopy. Time will tell.

Psychological and Social Consequences: A Pandora's Box?

Finally, the authors explore the important psychological and social consequences of a genetic diagnosis. They appropriately point out that the information provided by a definitive diagnosis of HNPCC frequently improves a person's outlook on life, whether the result proves that the individual carries such a mutated gene or rules out this possibility. A definitive answer is often gratifying, since individuals can make plans for coping with their circumstance, and 50% of those tested will experience relief from their anxieties.

It comes as a surprise to many individuals who are not involved in genetic counseling that not all patients who are informed that they carry a diseased gene react adversely. Conversely, some patients who are informed that they do not carry such a gene feel worse.

Moreover, there are important social consequences of genetic counseling that go beyond the personal psychological counseling. Will this information remain confidential? Will a gene carrier find that he or she is no longer considered employable or find it more difficult to obtain health or life insurance? Will there be aberrations in the social perception of individuals who carry mutated DNA mismatch repair genes, even if effective management can offer a reasonably good likelihood of leading a long and healthy life? At this point in time, a Pandora's box has been opened, and it remains to be seen how full it is.


1. Marra G and Boland CR: Hereditary nonpolyposis colorectal cancer (HNPCC): The syndrome, the genes, and an historical perspective. J Natl Cancer Inst 87:1114-1125, 1995.

2. Luce MC, Marra G, Chauban DP, et al: In vitro transcription/translation assay for the screening of hMLH1 and hMSH2 mutations in familial colon cancer. Gastroenterology 109:1368-1374, 1995.

3. Mecklin JP, Jarvinen HJ, and Peltokallio P: Cancer family syndrome: Genetic analysis of 22 Finnish kindreds. Gastroenterology 90:328:333, 1986.

4. Vasen HFA, Taal BG, Griffioen G, et al: Clinical heterogeneity of familial colorectal cancer and its influence on screening protocols. Gut 35:1262-1266, 1994.

5. Menko FH, Te Meerman GJ, Sampson JR: Variable age of onset in hereditary nonpolyposis colorectal cancer. Clinical implications. Gastroenterology 104:946-947, 1993.

6. Liu B, Farrington SM, Petersen GM, et al: Genetic instability occurs in the majority of young patients with colorectal cancer. Nature Medicine 1:348-353, 1995.

7. MacPhee M, Chepenik KP, Liddell RA, et al: The secretory phospholipase A2 gene is a candidate for Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81:957-966, 1995.

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