Genetic Counseling in Hereditary Nonpolyposis Colorectal Cancer

January 1, 1996

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].

Menko and colleagues review the genetic counseling that occursafter the presymptomatic diagnosis of hereditary nonpolyposiscolorectal cancer (HNPCC) is made. The discovery of the mechanismby which tumors develop in this setting and the cloning of thegenes responsible for the disease have made possible the DNA-baseddiagnosis of a disease, which, less than 5 years ago, was a controversialentity. In a remarkably short period, the nature of HNPCC hasbeen greatly elucidated, its relationship to defective DNA mismatchrepair has become manifest, and the means to diagnose it in apresymptomatic 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 areon the way. Before long, diagnostic tests will become commerciallyavailable, and we will have to grapple with a number of possiblyunforeseen issues. Physicians will be in a position toinform healthy adults with no premorbid phenotype that they areat extraordinary risk of developing cancer during their lifetime,and that this will tend to occur two to three decades earlierthan the rest of the population. Although physicians have beencounseling patients about their risk of neoplasia for many decades,they may be armed with a degree of certainty that was never previouslypossible. Will we be ready for this?

An Important Step Forward, But...

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

DNA-based diagnosis should, therefore, be considered an importantstep forward in the management of familial colon cancer. Certainly,there will be great enthusiasm to include these new approachesin our diagnostic armamentarium. However, we should consider thepossibility that risks may accompany the ability to make thisdiagnosis. 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 inwhich the Amsterdam criteria would not likely be met. New mutationscan be diagnosed and interpreted properly. In such instances,HNPCC has important implications for an individual and his orher offspring, but the risk does not extend to siblings or parents.Once a genetic diagnosis is confidently made, colonoscopic screeningand appropriate gynecologic screening may be initiated, as outlinedin the authors' Table 5. Moreover, psychological interventionand support may be started in the presymptomatic period, permittingthe affected individual to deal with risk and familial issuesindependently of problems associated with personal health risks.This information will surely empower the properly informed patientwith 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 withcomplexities that may not be immediately apparent to the primary-carephysician, surgeon, gastroenterologist, or oncologist. Numerousambiguities may cloud the interpretation of a genetic diagnosis.Each of the different genetic approaches to the diagnosis of HNPCChas its own inherent strengths and liabilities, as the authorsindicate. Every approach can miss the offending mutation, whichresults in a false-negative diagnosis.

Also, it is likely that we have not yet uncovered all of the genesthat can produce HNPCC. The DNA mismatch repair system requiresmany proteins, of which four have been linked to HNPCC and severalothers have not. Furthermore, at least one of these genes (hPMS-1)has been linked to only one HNPCC family, and due to the natureof this mutation, it is possible that it does not actually causethe HNPCC. On the other side of the equation, it would appearthat other members of the DNA mismatch repair system should becapable of causing HNPCC, but no families have yet been discoveredwith germ-line mutations in these genes. It will take time toestablish with certainty all of the genes that may result in HNPCC.

Some diagnostic approaches will always miss certain classes ofmutations. For example, direct sequencing of genes (the most rigorousbut labor-intensive approach to the diagnosis), will miss mutationsthat affect gene expression, may miss alterations at intron-exonborders that can adversely affect splicing, and will miss largegenetic deletions. Screening techniques, such as DGGE and SSCP,are intrinsically less sensitive than direct sequencing and aremore likely to result in underdiagnosis. The protein truncationtest (also called in vitro transcription/translation, or IVTT)detects only mutations that result in the translation of a pathologicallyforeshortened 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 approachfor the detection of germ-line mutations in the DNA repair genes.However, interpretation of the sequences may not be simple. Forexample, certain variations in DNA sequence will be silent andnot result in any change in the protein structure. Oth er variationsmay change the amino acid sequence of the protein (ie, a missensemutation), but this alteration may be "conservative"and not seriously affect its function. Therefore, the more sensitivedirect-sequencing approach may detect a "polymorphism"that represents a deviation from the most common human sequencesbut still may not cause disease.

Investigators familiar with DNA sequencing and molecular biologymay recognize these sequence variations as polymorphisms, butthis may not be obvious to the uninitiated. Worse yet, mutationsmay come in a variety of "strengths," some of whichare more powerful than others and may cause a more severe phenotype.The game is still young, and we are still in the process of tryingto understand the implications of different types of mutations.If clinicians unfamiliar with the principles of molecular biologycan 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, suchas linkage analysis or other techniques that study the segregationof DNA polymorphisms linked to a disease-causing gene in a family.This approach may be potentially hazardous as well, dependingon the propinquity of the marker locus to the disease-causinggene. This approach is usually used when a gene has been mappedbut has not yet been cloned. Linkage analysis should be used withsome caution.

HNPCC More Complicated Than Initially Thought

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

It is not known whether the variable penetrance is related todifferent "strengths" of the germ-line mutation, theinfluence of environmental factors, or even the modulating influenceof another gene, as appears to be the case in familial adenomatouspolyposis [7]. We must be prepared for the accumulation of perplexingdetails about this disease.

Management Still in Evolution

The management of patients with a DNA-based diagnosis of HNPCCis still in evolution. Interestingly, Menko et al suggest thatcolonoscopy 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 resourcesfor patients who are at 50% risk of the disease (ie, asymptomaticoffspring of HNPCC patients for whom a genetic diagnosis has notbeen possible) vs a more intense regimen than those who are knownto have HNPCC. Is this entirely rational? If 1- to 2-year colonoscopicintervals are appropriate for patients known to carry a gene forHNPCC, 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 untilthe affected gene is identified in a family. Thus, knowing moreabout the disease, but being unable to definitively rule it outin some patients, may increase the physician's anxieties aboutthe disease and actually increase the use of preventive measuresin such families. Finally, the authors stop short of recommendingthe most ambitious form of management, prophylactic colectomy(or perhaps subtotal colectomy). Although surgery would surelybe rejected by many patients, others may prefer a surgical approachto a lifetime of colonoscopy. Time will tell.

Psychological and Social Consequences: A Pandora's Box?

Finally, the authors explore the important psychological and socialconsequences of a genetic diagnosis. They appropriately pointout that the information provided by a definitive diagnosis ofHNPCC frequently improves a person's outlook on life, whetherthe result proves that the individual carries such a mutated geneor 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 involvedin genetic counseling that not all patients who are informed thatthey carry a diseased gene react adversely. Conversely, some patientswho are informed that they do not carry such a gene feelworse.

Moreover, there are important social consequences of genetic counselingthat go beyond the personal psychological counseling. Will thisinformation remain confidential? Will a gene carrier find thathe or she is no longer considered employable or find it more difficultto obtain health or life insurance? Will there be aberrationsin the social perception of individuals who carry mutated DNAmismatch repair genes, even if effective management can offera reasonably good likelihood of leading a long and healthy life?At this point in time, a Pandora's box has been opened, and itremains 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/translationassay for the screening of hMLH1 and hMSH2 mutations in familialcolon 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 heterogeneityof 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 onsetin hereditary nonpolyposis colorectal cancer. Clinical implications.Gastroenterology 104:946-947, 1993.

6. Liu B, Farrington SM, Petersen GM, et al: Genetic instabilityoccurs 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 phospholipaseA2 gene is a candidate for Mom1 locus, a major modifier of ApcMin-inducedintestinal neoplasia. Cell 81:957-966, 1995.