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© 2002 American Society for Clinical Oncology
Missense Mismatch Repair Gene Alterations, Microsatellite Instability, and Hereditary Nonpolyposis Colorectal CancerUniversity of Utah Health Sciences Center, Salt Lake City, UT To the Editor:The conclusion of Scartozzi et al1 that "germ-line mutations of the MMR [mismatch repair] gene can occur in people with MSI [microsatellite instability]-negative tumors" is valid only if the missense mutations they identified are pathogenic; as the authors acknowledge, these missense changes could represent rare polymorphisms. The determination of whether or not a missense mismatch repair gene alteration is disease-causing is one of the most challenging aspects of the genetics of hereditary nonpolyposis colorectal cancer (HNPCC); however, we would point out that two of the four supposedly pathogenic missense changes reported in this study (hMLH1: Lys618Ala and hMSH2: Asp167His) were reported by us in controls without colon cancer.2 It is also of concern that none of the five MSI-high tumors reported by the authors were associated with loss of expression of mismatch repair proteins, whereas six tumors without MSI-high were associated with loss of expression. This total discordance between MSI-high and loss of protein expression is inconsistent with previous studies3,4 and raises questions regarding the authors’ methodology. Furthermore, the fact that only one of 25 tumors exhibited instability with BAT-26, a microsatellite repeat marker with 100% sensitivity for HNPCC-associated tumors in a recent study,5 suggests that few if any of these individuals had HNPCC, regardless of their age or family history. We feel that a more reasonable interpretation of the authors’ results is that germline missense mutations that do not significantly impair the mismatch repair mechanism are not associated with MSI and are not related to HNPCC. REFERENCES
1. Scartozzi M, Bianchi F, Rosati S, et al: Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: Correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol 20: 1203-1208, 2002 2. Samowitz WS, Curtin K, Lin HH, et al: The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 121: 830-838, 2001[CrossRef][Medline]
3. Dietmaier W, Wallinger S, Bocker T, et al: Diagnostic microsatellite instability: Definition and correlation with mismatch repair protein expression. Cancer Res 57: 4749-4756, 1997
4. Bocker T, Diermann J, Friedl W, et al: Microsatellite instability analysis: A multicenter study for reliability and quality control. Cancer Res 57: 4739-4743, 1997
5. Luokola A, Eklin K, Laiho P, et al: Microsatellite marker analysis in screening for hereditary nonpolyposis colorectal cancer (HNPCC). Cancer Res 61: 4545-4549, 2002
ResponseClinica di Oncologia Medica, University of Ancona, Ancona, Italy In Reply:We thank Drs Samowitz and Slattery for their comments to our article.1 We are aware that assessing the role of missense mutations of mismatch repair (MMR) genes represents a challenging but critical aspect of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Unfortunately, the criteria currently used to predict the pathogenicity of such genetic abnormalities are often inconclusive, and in vitro assays to test the functional consequences of single amino acid substitutions are not widely available. The K618A hMLH1 mutation, which was found by Samowitz et al2 in a healthy control and by us in a patient with suspected HNPCC,1 was shown by other authors to segregate with the HNPCC phenotype3-5 and to impair the interaction of hMLH1 with hPMS2 in vitro.6 In addition, codon 618 of hMLH1 is the target of other pathogenic mutations, such as K618T, 618 deletion of lysine, which are often found in HNPCC.3 Taken together, these data strongly suggest that the K618A mutation belongs to the group of genetic abnormalities implicated in the pathogenesis of the HNPCC syndrome. The hMSH2 A167H mutation, which we found in a case of early-onset colon cancer,1 may represent a rare polymorphism, because it was also found in one healthy control2; however, we feel that the data available are not sufficient to conclusively establish its role. Drs Samowitz and Slattery argue that the germ line mutations we found may be unrelated to HNPCC because they are not associated with high microsatellite instability (MSI). The likelihood that "such a low level of MSI may suggest that these mutations were not implicated in the familial susceptibility to colon cancer" is clearly stated in our article.1 Nevertheless, it should be re-emphasized that certain missense mutations of MMR genes do not correlate with MSI, although they segregate with the disease and inactivate the MMR machinery in vitro; these include the K618A,5,6 the V326A,7,8 and the E578G hMLH1 mutations.5,6 Discrepancies between the occurrence of MSI and immunohistochemical abnormalities of MMR gene expression have been previously reported, as well as germ line mutations of hMLH1 or hMSH2 not correlating with alterations of the BAT 26 microsatellite marker.7,9,10 Most population-based studies dealing with the HNPCC syndrome analyze large cohorts of colon cancer patients for MSI and search for MMR gene mutation in individuals with MSI positive tumors.2 This study design ensures a high correlation between germ line mutations and occurrence of MSI and allows the identification of patients with mutations that are mostly chain-terminating and are associated with a strong phenotype. Therefore, it is likely that these studies will miss patients harboring germ line mutations associated with an attenuated phenotype and low or no MSI. The identification of individuals with suspected HNPCC should be primarily clinical, based on the personal and familial cancer history.11 Recognizing the clinical features of HNPCC is critical to assess the risk of colon cancer, to counsel the at-risk individuals, and to recommend the appropriate surveillance program. In these patients, genetic testing represents a useful complement, which could contribute to establish the diagnosis. However, the clinician should not disregard the suspicion of HNPCC if the test results are negative or uncertain. In our article, we studied the genetics of a series of patients with the clinical features of HNPCC, to formulate a selection procedure for individuals who should be offered genetic testing.1 The fact that some of the mutations we found do not have a certain biologic significance and that some of our observations do not meet the current consensus, may depend on the clinical criteria we used to carry out our study. As with our patients, many individuals with suspected HNPCC often display an attenuated phenotype and show mutations of MMR genes whose biologic consequences are uncertain.4,5 More clinically oriented research is warranted to clarify the role of these genetic abnormalities and to understand their relationship with the HNPCC syndrome. REFERENCES
1. Scartozzi M, Bianchi F, Rosati S, et al: Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: Correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol 20: 1203-1208, 2002 2. Samowitz WS, Curtin K, Lin HH, et al: The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 121: 830-838, 2001[CrossRef][Medline] 3. Peltomaki P, Vasen HFA, and the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer: Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. Gastroenterology 113: 1146-1158, 1997[CrossRef][Medline] 4. Winjen J, Khan PM, Vasen H, et al: Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. Am J Hum Genet 61: 329-335, 1997[Medline] 5. Liu T, Tannergard P, Hackman P, et al: Missense mutations in hMLH1 associated with colorectal cancer. Hum Genet 105: 437-441, 1999[CrossRef][Medline]
6. Guerrette S, Acharya S, Fishel R, et al: The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem 274: 6336-6341, 1999 7. Capozzi E, Della Puppa L, Fornasarig M, et al: Evaluation of the replication error phenotype in relation to molecular and clinicopathological features in hereditary and early onset colorectal cancer. Eur J Cancer 35: 289-295, 1999[Medline]
8. Ellison AR, Lofing J, Bitter GA: Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. Hum Mol Genet 10: 1889-1900, 2001
9. Percesepe A, Borghi F, Menigatti M, et al: Molecular screening for hereditary nonpolyposis colorectal cancer: A prospective, population-based study. J Clin Oncol 19: 3944-3950, 2001 10. Bapat BV, Madlensky L, Temple LKF, et al: Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer. Hum Genet 104: 167-176, 1999[CrossRef][Medline] 11. Terdiman JP: HNPCC: An uncommon but important diagnosis. Gastroenterology 121: 1005-1008, 2001[Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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