Molecular Screening for the Lynch Syndrome ― Better Than Family History?
【关键词】 Molecular,
Colorectal cancer is the third most common cause of death from cancer in the United States, after lung cancer and breast cancer.1 A well-defined hereditary predisposition accounts for probably 3 to 4 percent of cases of colorectal cancer. Conditions such as familial adenomatous polyposis and the Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) nevertheless represent important models, and their contribution to the understanding of mechanisms of carcinogenesis is out of proportion to their frequency. Within a family with the Lynch syndrome, opportunities for genetic testing and enhanced surveillance exist. Because of the early age at the onset of colorectal cancer among patients with this syndrome (approximately 45 years of age) and the predilection of the cancer for the proximal colon, colonoscopy is initiated at the age of 25. Because of accelerated carcinogenesis, it needs to be repeated annually.2,3,4
Family history can provide important clues to the presence of the Lynch syndrome. However, such clues may be missed because of small family size, the physician's unfamiliarity with the nuances of the Lynch syndrome, lack of documentation, or reduced penetrance of germ-line mutations in the mismatch-repair genes (MSH2, MLH1, MSH6, PMS2) so that otherwise informative carriers may not express the cancer phenotype.
About 90 to 95 percent of colorectal cancers in patients with the Lynch syndrome show evidence of microsatellite instability, a readily detectable change in the number of DNA repeat sequences (microsatellites) in certain genes. In principle, and increasingly in practice, assays for microsatellite instability can be used to determine whether a patient in whom the Lynch syndrome is suspected in fact has a high probability of having an underlying mismatch-repair mutation. Because tumors in patients with the Lynch syndrome typically show loss of heterozygosity for the mismatch-repair gene responsible for the syndrome, the corresponding protein is lost altogether. This loss can be readily demonstrated with the use of immunohistochemical staining and has been shown to correlate with the presence of microsatellite instability.
In this issue of the Journal, members of the team that discovered the mismatch-repair genes responsible for the Lynch syndrome provide additional insight with regard to molecular-based screening for the condition. Hampel et al.5 performed microsatellite-instability studies and immunohistochemical staining for mismatch-repair proteins on tumor tissue obtained from 1066 otherwise unselected patients with colorectal cancer in metropolitan Columbus, Ohio. Patients whose tumors showed a high level of microsatellite instability or loss of staining for one of the proteins related to the mismatch-repair genes underwent testing for these mutations. Consistent with data from series described to date, nearly 20 percent of all tumors showed microsatellite instability. Most cancers that exhibit microsatellite instability are not thought to be due to the Lynch syndrome but, rather, to epigenetic silencing of the MLH1 gene, which is detectable through assays to detect hypermethylation. In this Ohio series of patients whose tumors showed microsatellite instability but not hypermethylation, and thus were likely to represent the Lynch syndrome, approximately 79 percent were found to have disease-causing mutations in one of the mismatch-repair genes. This finding is also consistent with data from a more truly population-based series of patients with colorectal cancer in Finland.6
Why are these findings important? Until the mismatch-repair genes were identified, beginning in the early 1990s, suspicion of the Lynch syndrome rested entirely on the presence of characteristic patterns of cancer within families, abetted by the key but nonspecific clinical features described above. These phenotypic features contributed to the so-called Amsterdam criteria and, more recently, to the modified or Amsterdam II criteria. However, these clinical criteria are both over-inclusive and under-inclusive. In this Ohio series, the Amsterdam criteria were met by only 3 of 23 subjects found to have mismatch-repair mutations signifying the Lynch syndrome. Screening for microsatellite instability and immunohistochemical testing pointed to the remainder of subjects with the Lynch syndrome. Some subjects (15 of the 23) did meet the Bethesda criteria for the Lynch syndrome, which can be thought of as an amalgam of, and perhaps a bridge between, the strictly clinical features (including family clustering) and the molecular approach taken by Hampel et al. Some of the Bethesda criteria are focused on clinical features such as age, location, and multiplicity of tumors, whereas other criteria consider pathological features such as poor differentiation, the presence of tumor-infiltrating lymphocytes, signet-ring cells, and mucinous component.
In the United States, the charge for testing for germ-line mutations, depending on the assay or assays used, may cost upward of $2,000, and insurance coverage for such testing is unpredictable. Indeed, in this study, germ-line mutation testing was not universally done because of considerations of cost. Rather, it was limited to the 20 percent of subjects with tumors showing microsatellite instability. The assumption, not tested here, appears to have been that microsatellite instability and immunohistochemical staining are sufficiently sensitive to the presence of the Lynch syndrome that germ-line mutation testing of subjects with microsatellite-stable tumors is not warranted. But the charge for testing for microsatellite instability or immunohistochemical analysis alone is a minimum of $300 and often considerably more. Unless one is willing to perform microsatellite-instability testing on all newly diagnosed colorectal cancers, selection factors must be prudently determined.
The study by Hampel et al.5 leaves several questions unanswered. Although microsatellite instability in colorectal cancer seems to be a good predictor of the presence of the Lynch syndrome, adenomas do not show the characteristic abnormalities as reliably. Also, as noted earlier, we do not know whether there is a meaningful frequency of mismatch-repair mutations in subjects with microsatellite-stable tumors with normal results on immunohistochemical staining. Since the number of such cases is evidently quite low, the answer may not be worth pursuing clinically. However, it could be helpful to research. Neither the study by Hampel et al. nor the studies it cites6,7 involved comprehensive testing of all subjects for germ-line mutations.
The key question for the clinician is the role of microsatellite instability and immunohistochemical staining, separately or in combination, as intermediate methods of screening for the Lynch syndrome. Should either test be performed routinely among all patients with colorectal cancer? Probably not, because the yield among subjects more than 55 years of age has been shown in this study and others to be very low. Microsatellite instability in tumors of older subjects is more likely to be related to hypermethylation of the MLH1 promoter and to have nothing to do with the Lynch syndrome, thus carrying a very low positive predictive value in such patients, especially in the absence of family history pointing to the syndrome. Indeed, unless one is prepared to perform an assay for methylation of the MLH1 promoter, the finding of microsatellite instability or loss of the MLH1 protein on immunohistochemical staining merely confuses interpretation among older patients.
If microsatellite-instability testing and immunohistochemical staining are not to be performed universally, then what index of suspicion needs to be present to warrant their use? In this study, and somewhat contrary to findings in other studies to date, a family history or at least the Amsterdam criteria for the Lynch syndrome appear to have been poor predictors of the syndrome. Only 13 percent of subjects found to have the Lynch syndrome on microsatellite-instability testing or immunohistochemical screening would have been independently selected for further consideration on the basis of the presence of factors fulfilling the Amsterdam criteria. An age of less than 50 years was somewhat more sensitive than these criteria.
But who will pay for this screening? Third-party payers want a method of molecular diagnosis that is highly sensitive and specific and that affects clinical management in a useful way. They also want to know that costly lifetime colonoscopic screening really works. In a controlled, 15-year trial of screening for colorectal cancer among patients with the Lynch syndrome, J?rvinen et al.8 demonstrated that colonoscopic screening indeed reduced mortality.
If the use of microsatellite-instability testing and immunohistochemical staining is so informative, what barriers to their use exist? Lack of familiarity on the part of clinicians may be one that can be overcome by data of the sort reported by Hampel et al. Whether insurers will be persuaded that the screening strategy is cost-effective remains to be seen. To the extent that insurance coverage is an issue, the willingness of patients to have information about a potential diagnosis of the Lynch syndrome divulged becomes central. The resolution of such matters is beyond the scope of the data provided by Hampel et al. but, one hopes, will be abetted by them.
Drs. Henry Lynch and Patrick Lynch report having received lecture fees from Myriad Genetics.
Source Information
From the Creighton University School of Medicine, Omaha, Nebr. (H.T.L.); and the University of Texas M.D. Anderson Cancer Center, Houston (P.M.L.).
References
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919-932.
Jass JR, Stewart SM, Stewart J, Lane MR. Hereditary non-polyposis colorectal cancer -- morphologies, genes and mutations. Mutat Res 1994;310:125-133.
Jass JR, Smyrk TC, Stewart SM, Lane MR, Lanspa SJ, Lynch HT. Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res 1994;14:1631-1634.
Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352:1851-1860.
Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998;338:1481-1487.
Salovaara R, Loukola A, Kristo P, et al. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000;18:2193-2200.
J?rvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829-834.
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