Gastroenterology
Volume 129, Issue 2 , Pages 741-744, August 2005

It Is Time to Get Serious About Diagnosing Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer With Defective DNA Mismatch Repair) in the General Population

  • Jonathan P. Terdiman

      Affiliations

    • Corresponding Author InformationAddress reprint requests to: Jonathan P. Terdiman, MD, Associate Professor of Clinical Medicine, University of California, San Francisco, 2330 Post Street, Suite 610, San Francisco, California 94115. fax: (415) 502-2249.

University of California at San Francisco, San Francisco, California

Article Outline

 

Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome after Henry T. Lynch, MD, a pioneer in the field, is an autosomal dominant hereditary cancer syndrome, which accounts for upwards of 3% of all colorectal cancers,1, 2 and is associated with an increased risk of endometrial, ovarian, and other extra-colonic cancers.3 Colorectal cancer can be averted in Lynch syndrome by early an intensive surveillance, and has been shown to be cost-effective.4, 5 The syndrome originally was defined in clinical terms by the stringent Amsterdam criteria,6, 7 although over time more relaxed clinical definitions have been suggested, culminating in the recently published revised Bethesda guidelines.8, 9 Many cases of clinically defined Lynch syndrome are caused by a germline mutation in one of a set of genes responsible for DNA mismatch repair, with most of the disease causing mutations occurring in either MSH2 or MLH1, a smaller number in MSH6, and a few in PMS2.10 Deficient mismatch repair, manifest as high-frequency microsatellite instability (MSI-H), can be demonstrated in DNA from upwards of 95% Lynch-related colorectal cancers,11 and nearly all of the tumors also will demonstrate a loss of expression of one or more of the protein products of the DNA mismatch repair genes by immunohistochemistry (IHC).11 Because 10%–20% of sporadic colorectal cancers are also MSI-H, due to somatic inactivation of MLH1 via promoter methylation,12 the finding of MSI-H, or loss of MLH1 expression in a tumor, is suggestive, but is not diagnostic of Lynch syndrome.13 Lack of MLH1 promoter methylation and/or lack of a somatic activating mutation in the proto-oncogene BRAF (V600E) in Lynch-related cancers, however, can distinguish most of these from sporadic MSI-H cancers with a high degree of accuracy.14

Commercial testing for germline DNA mismatch repair gene mutations, for assessment of microsatellite instability in tumoral DNA and IHC for the DNA mismatch repair proteins is widely available. Whenpresent, a disease causing mutation can be identified upwards of 90% of the time using optimal laboratory methods.15 The detection of Lynch syndrome gene carriers improves the efficiency of cancer surveillance by identifying which family members require it, and who can receive standard care.16, 17 Nevertheless, most Lynch syndrome gene carriers in the population are not being identified. The number of molecular evaluations requested each year across the United States remains very low, despite the fact that such an evaluation currently is recommend for the approximately 20% of all colorectal cancer patients diagnosed each year who meet the revised Bethesda guidelines.18, 19, 20, 21

So why is Lynch syndrome not being diagnosed? Inconsistency of insurance coverage for testing, and fear of genetic discrimination are reasons often cited, but are not likely the major culprits. Reliable data do not exist, but it appears that most insurers will cover testing costs, incidents of actual discrimination of extremely rare, and there is a growing body of law which protects against genetic discrimination on the state and national level.3 Although patient-reported family cancer histories appear to be accurate and valuable for colorectal cancer risk assessments,22 nearly one half of oncologists fail to document a comprehensive family history, and among those that do, few take appropriate action if it is positive with respect to referral for genetic evaluation.20 Time constraints placed on today’s busy health care providers are likely a major part the problem, but so is the focus on disease treatment rather than prevention, especially among cancer patients. Many health care providers do not recognize the benefits of genetic testing for their patient with cancer. Providers may recognize the potential benefits of genetic evaluation of unaffected family members, but often they remain skeptical of the benefits actually realized. Complaints that genetic testing for hereditary colorectal cancer requires effort, but frequently results are not informative, are often voiced (see below for additional explanation). Finally, even if a cancer family history is obtained, and acted upon as currently recommended, it may be that current diagnostic guidelines are flawed and destined to miss a significant number of Lynch syndrome patients no matter how rigorously they are applied.

Over the past few months, there have been a number of important studies published, including one by Hampel et al23 in this issue of Gastroenterology, which have provided information about Lynch syndrome pertinent to understanding and overcoming the barriers to the widespread identification of the syndrome outlined previously. A seminal study by Lindor et al24 speaks to the informativeness of the genetic evaluation for Lynch syndrome, and demonstrates that these evaluations will provide information critical to the future health care of both the cancer patient and their family members.24 Lindor et al compared families meeting the Amsterdam criteria who did or did not have evidence of mismatch repair deficiency. Their finding that the relatives from families who fulfill the Amsterdam criteria, but who have no evidence of DNA mismatch repair deficiency, have a significantly lower risk of colorectal cancer compared with relatives from families with hereditary mismatch repair deficiency, and no appreciable risk for extracolonic cancers, is of major importance. In the past, the finding of a causative germline mutation in a cancer-affected patient was useful because it verified the presence of the syndrome in the patient and allowed accurate predisposition testing of non-affected relatives. However, failure to find evidence of mismatch repair deficiency in an individual suspected of having Lynch syndrome based on clinical criteria was not informative. One still had to assume that the patient had the syndrome, and that all at-risk relatives may have it as well, with all of the attendant cancer risks and need for ongoing intensive cancer surveillance for both colonic and extra-colonic cancer in the patient and members of his or her family.3 Lindor’s study has freed us from this bind, and makes the case for genetic evaluation of suspected Lynch syndrome patients much stronger. Patients with a strong cancer family history but without mismatch repair deficiency, and their family members, can receive less intensive cancer surveillance than what is recommended in Lynch syndrome. For the patient with colorectal cancer and no evidence of mismatch repair deficiency, total abdominal colectomy at the time of diagnosis, yearly surveillance of any remaining colorectum for life, and yearly surveillance for several other extra-colonic cancers would not be required, as are recommended for Lynch patients.3 Another byproduct of Lindor’s study is that it establishes the appropriate definition of the Lynch syndrome, which is hereditary deficient mismatch repair caused by a germline mutation in one of the DNA mismatch repair genes. The designation of “familial colorectal cancer type X” was suggested to describe the other families with a strong familial aggregation of colorectal cancer, and it remains to be seen if this name catches on. More importantly, the genetic origin(s) of this entity remains to be determined.

What else can be learned from the recent studies of Lynch syndrome? The study by Hampel et al23 that appears in this issue of Gastroenterology suggests that the phenotype of Lynch syndrome is in the general population may be different than previously assumed, and because of this, current diagnostic guidelines may miss many cases of the syndrome even if they are well applied. Hampel et al23 determined the lifetime cancer risk and age of cancer onset in a group of Lynch syndrome gene carriers ascertained from 2 sources, a high-risk registry and the general population in Finland, comprising a total 70 Lynch families with 88 probands and 373 mutation-positive individuals. After appropriately excluding the probands from the analysis, the median age of diagnosis of colorectal cancer was 54 years (95% CI, 50–61.2) among men and 70 years among women (95% CI, 62.8-infinity), much higher than the previously reported 40 to 45 years of age among Lynch syndrome patients.3 If the age of onset of colorectal cancer is much higher among Lynch syndrome gene carriers than previously recognized, then current clinical diagnostic guidelines, like the Amsterdam criteria and revised Bethesda guidelines, which make much of early age of cancer onset in the syndrome, may not be optimal. Why might our understanding of the clinical phenotype of the Lynch syndrome in the general population be off the mark? As demonstrated by Hampel et al, a major problem is ascertainment bias, with much of the data used to define the clinical features of the syndrome obtained from high-risk registry populations that often used early age of cancer onset as a criterion for enrollment, rather than using truly representative population-based samples. If one is systematically identifying Lynch syndrome cases by looking for young people with cancer, instead of looking at all the Lynch gene carriers in the population, it is not surprising that our estimates of age of onset will be incorrectly low.

Two additional population-based studies recently published, one performed by Hampel et al in the United States,25 and one by Pinol et al21 in Spain,21 further clarify the clinical features of Lynch syndrome, and may suggest an easier and more accurate way of establishing the diagnosis than the current reliance on clinical diagnostic schemes. Hampel et al23 in fact suggest that routine molecular screening for Lynch syndrome of all patients with colorectal cancer should be undertaken because of the poor sensitivity of the current clinical guidelines even if uniformly applied. In their study, 1066 patients with a new diagnosis of colorectal cancer in Ohio were enrolled. All had their tumors analyzed for MSI, and 19.5% were found to have microsatellite instability. Subsequent germline mutational analysis among those with MSI-H tumors identified Lynch syndrome in 23 (2.2% of the total colorectal cancer population). There were several surprising findings in the study. Five of the 23 mutation carriers had mutations in MSH6 or PMS2. Only 3 of the mutation carriers met the Amsterdam criteria, and 10 were older than 50 years of age when they developed cancer. Five of the mutation carriers, including three with mutations in MSH6 or PMS2, did not meet the revised Bethesda guidelines. Pinol et al21 executed a study with similar design in 1222 Spanish patients with a new diagnosis of colorectal cancer. Unlike in the study by Hampel et al, the revised Bethesda guidelines appeared to work well and would have identified 91% of the mutation-positive Lynch syndrome patients. The Spanish investigators concluded that the revised Bethesda guidelines were an excellent way to select colorectal cancer patients for molecular analysis for Lynch syndrome. However, a couple of important features distinguish the studies of Hampel and Pinol, and may account for much of the differences in results and conclusions. Pinol et al23 only detected MSI in 7.4% of their study population, a very low frequency that may suggest a methodological problem. In addition analyses for MSH6 or PMS2 mutations were not undertaken, and it may be that carriers of mutations in these genes are even less likely to meet the revised Bethesda guidelines compared with MSH2 or MLH1 gene carriers.

After reviewing these recent data, and acknowledging the real barriers to the diagnosis of Lynch syndrome in the general population as previously discussed, what diagnostic strategy should be recommend? It is time to call for universal molecular screening by MSI or IHC of all colorectal cancer patients, with IHC of the tumor for the 4 mismatch repair gene proteins likely being easier to implement at the present time. The sensitivity of IHC for identifying colorectal cancers with mismatch repair deficiency (MSI-H tumors) exceeds 90%.21, 25 Though the revised Bethesda guidelines may do a good job of finding Lynch patients with either MSH2 or MLH1 mutations, with a sensitivity of approximately 90%,21, 23, 25, 26, 27 to work they need to be used effectively, which they are not.20 In addition, the guidelines may not be very good at finding those with mutations in the “minor” genes, MSH6 or PMS2,25 and these genes may account for more cases of Lynch syndrome in the population than previously recognized.25 Worries that IHC for the mismatch repair genes is a surrogate for germline genetic testing and should not undertaken without a discussion of the risk of genetic discrimination are not without merit (a problem avoided by screening by MSI testing), but are over emphasized and should yield to the benefits accrued to the patient and family members through accurate diagnosis.

How should screening with IHC proceed? IHC for the mismatch repair proteins already is available at several referral laboratories, but widespread screening may require implementation on the local level, with no loss of quality, and with regular reimbursement for these services. Loss of expression of any of the mismatch repair proteins should be a red flag and trigger further evaluation, and systems need to be established to deal with positive results in an appropriate manner. Automatic reporting of positive results to a cancer genetics professional may be the best approach. The genetic counselor, or other trained individual, would contact the patient, and their provider, to discuss the implications of the results, and help to disseminate results to other family members as needed. Adequate reimbursement for these services would be essential. Individuals with loss of MSH2 or MSH6 in their tumors should be offered germline mutation testing after counseling, directed to the gene of interest. Those with loss of MLH1 or PMS2 might be offered germline gene testing, but it is important to remember that the vast majority of tumors with loss of MLH1 expression are sporadic, and not secondary to Lynch syndrome. Therefore, it would be wise to limit gene testing in this group to those with either a family history meeting the revised Bethesda guidelines (all of the MLH1 gene carriers did meet the revised Bethesda guidelines in the study by Hampel et al), or to those whose tumors fail to demonstrate hypermethylation or somatic BRAF mutations. Ready access to these additional molecular tissue diagnostics would greatly reduce the number of germline gene tests required.

Universal molecular screening of all newly diagnosed colorectal cancers will jump-start the process of identifying Lynch syndrome in the general population, but the cancer family history remains crucial. Molecular screening cannot diagnose Lynch syndrome in those who are yet to develop neoplasia, and the utility of IHC for the mismatch repair proteins is of uncertain usefulness in individuals with cancers other than colorectal, and in patients with premalignant lesions, such as colonic adenomas.28 In addition, we need to recognize patients with familial risk outside of Lynch syndrome. So along with universal molecular screening for Lynch syndrome, we need to establish better systems to ensure universal assessment of the cancer family history in all people.

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References 

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PII: S0016-5085(05)01195-9

doi:10.1053/j.gastro.2005.06.033

Refers to article:

  • Cancer Risk in Hereditary Nonpolyposis Colorectal Cancer Syndrome: Later Age of Onset

    Heather Hampel, Julie A. Stephens, Eero Pukkala, Risto Sankila, Lauri A. Aaltonen, Jukka-Pekka Mecklin, Albert de la Chapelle
    Gastroenterology August 2005 (Vol. 129, Issue 2, Pages 415-421)

Gastroenterology
Volume 129, Issue 2 , Pages 741-744, August 2005

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