Missense Mismatch Repair Gene Alterations, Microsatellite Instability, and Hereditary Nonpolyposis Colorectal Cancer
Authors: Wade S. Samowitz, Martha L. Slattery, Emilio Porfiri, Mario Scartozzi, Andrea Piga, Riccardo Cellerino
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.14.3178 Journal of Clinical Oncology - published online before print November 1, 2016 PMID: 12118033 Missense Mismatch Repair Gene Alterations, Microsatellite Instability, and Hereditary Nonpolyposis Colorectal Cancer Wade S. SamowitzxWade S. SamowitzSearch for articles by this author , Martha L. SlatteryxMartha L. SlatterySearch for articles by this author Emilio PorfirixEmilio PorfiriSearch for articles by this author , Mario ScartozzixMario ScartozziSearch for articles by this author , Andrea PigaxAndrea PigaSearch for articles by this author , Riccardo CellerinoxRiccardo CellerinoSearch for articles by this author Show More University of Utah Health Sciences Center, Salt Lake City, UTClinica di Oncologia Medica, University of Ancona, Ancona, Italy https://doi.org/10.1200/JCO.2002.20.14.3178 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15072002In 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.7,9,10Most 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.1. Scartozzi M, Bianchi F, Rosati S, et al: Mutations of and in patients with suspected hereditary nonpolyposis colorectal cancer: Correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol 20:: 1203,2002-1208, hMLH1 hMSH2 Link, Google Scholar2. Samowitz WS, Curtin K, Lin HH, et al: The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 121:: 830,2001-838, Crossref, Medline, Google Scholar3. 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:: 1146,1997-1158, Crossref, Medline, Google Scholar4. 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:: 329,1997-335, Crossref, Medline, Google Scholar5. Liu T, Tannergard P, Hackman P, et al: Missense mutations in associated with colorectal cancer. Hum Genet 105:: 437,1999-441, hMLH1 Crossref, Medline, Google Scholar6. Guerrette S, Acharya S, Fishel R, et al: The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem 274:: 6336,1999-6341, Crossref, Medline, Google Scholar7. 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:: 289,1999-295, Crossref, Medline, Google Scholar8. 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:: 1889,2001-1900, Crossref, Medline, Google Scholar9. Percesepe A, Borghi F, Menigatti M, et al: Molecular screening for hereditary nonpolyposis colorectal cancer: A prospective, population-based study. J Clin Oncol 19:: 3944,2001-3950, Link, Google Scholar10. Bapat BV, Madlensky L, Temple LKF, et al: Family history characteristics, tumor microsatellite instability and germline and mutations in hereditary colorectal cancer. Hum Genet 104:: 167,1999-176, MSH2 MLH1 Crossref, Medline, Google Scholar11. Terdiman JP: HNPCC: An uncommon but important diagnosis. Gastroenterology 121:: 1005,2001-1008, Crossref, Medline, Google Scholar