FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 339:511-518 August 20, 1998 Number 8 Next

	Full Text PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6 ) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing.

Methods We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families.

Results Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1.

Conclusions Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.

Source Information

From the Departments of Human Genetics (J.T.W., P.M.K., H.K., A.M., R.F.), Gastroenterology (H.F.A.V.), and Medical Statistics (A.H.Z.) and the Clinical Genetics Center (C.T.), Leiden University Medical Center, Leiden, the Netherlands; the Foundation for the Detection of Hereditary Tumors, Leiden, the Netherlands (H.F.A.V.); and the Unit of Medical Genetics, Norwegian Radium Hospital, Oslo, Norway (P.M.). Other authors were Fred Menko, M.D., Ph.D. (University Hospital Vrije Universiteit, Amsterdam, the Netherlands), Babs Taal, M.D., Ph.D. (Netherlands Cancer Institute, Amsterdam, the Netherlands), Fokko Nagengast, M.D., Ph.D., and Han Brunner, M.D., Ph.D. (Nijmegen University Hospital, Nijmegen, the Netherlands), Jan Kleibeuker, M.D., Ph.D., and Rolf Sijmons, M.D. (University Hospital Groningen, Groningen, the Netherlands), Gerrit Griffioen, M.D., Ph.D., Annette Bröcker-Vriends, M.D., Ph.D., Egbert Bakker, Ph.D., and Inge van Leeuwen-Cornelisse, B.S. (Leiden University Medical Center, Leiden, the Netherlands), Anne Meijers-Heijboer, M.D., Dick Lindhout, M.D., Ph.D., and Martijn Breuning, M.D., Ph.D. (Erasmus University, Rotterdam, the Netherlands), Jan Post, M.D. (Clinical Genetics Center Utrecht, Utrecht, the Netherlands), Cees Schaap, M.D. (Clinical Genetics Center Maastricht, Maastricht, the Netherlands), Jaran Apold, M.D., Ph.D. (Haukeland University Hospital, Bergen, Norway), Ketil Heimdal, Ph.D. (Norwegian Radium Hospital, Oslo, Norway), Lucio Bertario, M.D., Ph.D. (Istituto Nazionale Tumori, Milan, Italy), Marie Luise Bisgaard, M.D. (Danish Hereditary Nonpolyposis Colorectal Cancer Registry, Hvidovre Hospital, Hvidovre, Denmark), and Petr Goetz, M.D., Ph.D. (Charles University, Prague, Czech Republic).This work is dedicated to the memory of Dr. P. Meera Khan.

Address reprint requests to Dr. Vasen at the Foundation for the Detection of Hereditary Tumors, Rijnsburgerweg 10, Poortgebouw Zuid, 2333 AA Leiden, the Netherlands.

Full Text of this Article

This article has been cited by other articles:

• Ramsoekh, D, van Leerdam, M E, Wagner, A, Kuipers, E J, Steyerberg, E W (2009). Mutation prediction models in Lynch syndrome: evaluation in a clinical genetic setting. J. Med. Genet. 46: 745-751 [Abstract] [Full Text]  
• Green, R. C., Parfrey, P. S., Woods, M. O., Younghusband, H. B. (2009). Prediction of Lynch Syndrome in Consecutive Patients With Colorectal Cancer. JNCI J Natl Cancer Inst 101: 331-340 [Abstract] [Full Text]  
• Ramsoekh, D, Wagner, A, van Leerdam, M E, Dinjens, W N M, Steyerberg, E W, Halley, D J J, Kuipers, E J, Dooijes, D (2008). A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut 57: 1539-1544 [Abstract] [Full Text]  
• Balmana, J., Steyerberg, E. W., Syngal, S. (2008). Risk Quantification for Carrying Mutations in Lynch Syndrome Genes. Am Soc Clin Oncol Ed Book 2008: 59-64 [Abstract] [Full Text]  
• Lynch, H. T., Boland, C. R., Rodriguez-Bigas, M. A., Amos, C., Lynch, J. F., Lynch, P. M. (2007). Who Should Be Sent for Genetic Testing in Hereditary Colorectal Cancer Syndromes?. JCO 25: 3534-3542 [Abstract] [Full Text]  
• Vasen, H F A, Moslein, G, Alonso, A, Bernstein, I, Bertario, L, Blanco, I, Burn, J, Capella, G, Engel, C, Frayling, I, Friedl, W, Hes, F J, Hodgson, S, Mecklin, J-P, Moller, P, Nagengast, F, Parc, Y, Renkonen-Sinisalo, L, Sampson, J R, Stormorken, A, Wijnen, J (2007). Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J. Med. Genet. 44: 353-362 [Abstract] [Full Text]  
• Seiden, M. V., Patel, D., O'Neill, M. J., Oliva, E. (2007). Case 13-2007 -- A 46-Year-Old Woman with Gynecologic and Intestinal Cancers. NEJM 356: 1760-1769 [Full Text]  
• Aaltonen, L., Johns, L., Jarvinen, H., Mecklin, J.-P., Houlston, R. (2007). Explaining the Familial Colorectal Cancer Risk Associated with Mismatch Repair (MMR)-Deficient and MMR-Stable Tumors. Clin. Cancer Res. 13: 356-361 [Abstract] [Full Text]  
• De Felice, C, Gentile, M, Barducci, A, Bellosi, A, Parrini, S, Chitano, G, Latini, G (2006). Abnormal oral mucosal light reflectance: a new clinical marker of high risk for colorectal cancer. Gut 55: 1436-1439 [Abstract] [Full Text]  
• Balmana, J., Stockwell, D. H., Steyerberg, E. W., Stoffel, E. M., Deffenbaugh, A. M., Reid, J. E., Ward, B., Scholl, T., Hendrickson, B., Tazelaar, J., Burbidge, L. A., Syngal, S. (2006). Prediction of MLH1 and MSH2 mutations in Lynch syndrome.. JAMA 296: 1469-1478 [Abstract] [Full Text]  
• Chen, S., Wang, W., Lee, S., Nafa, K., Lee, J., Romans, K., Watson, P., Gruber, S. B., Euhus, D., Kinzler, K. W., Jass, J., Gallinger, S., Lindor, N. M., Casey, G., Ellis, N., Giardiello, F. M., Offit, K., Parmigiani, G., for the Colon Cancer Family Registry, (2006). Prediction of germline mutations and cancer risk in the Lynch syndrome.. JAMA 296: 1479-1487 [Abstract] [Full Text]  
• Lindor, N. M., Petersen, G. M., Hadley, D. W., Kinney, A. Y., Miesfeldt, S., Lu, K. H., Lynch, P., Burke, W., Press, N. (2006). Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review.. JAMA 296: 1507-1517 [Abstract] [Full Text]  
• Hendriks, Y. M.C., de Jong, A. E., Morreau, H., Tops, C. M.J., Vasen, H. F., Wijnen, J. Th., Breuning, M. H., Brocker-Vriends, A. H.J.T. (2006). Diagnostic Approach and Management of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma): A Guide for Clinicians. CA Cancer J Clin 56: 213-225 [Abstract] [Full Text]  
• Barnetson, R. A., Tenesa, A., Farrington, S. M., Nicholl, I. D., Cetnarskyj, R., Porteous, M. E., Campbell, H., Dunlop, M. G. (2006). Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.. NEJM 354: 2751-2763 [Abstract] [Full Text]  
• Chao, E. C., Lipkin, S. M. (2006). Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res 34: 840-852 [Abstract] [Full Text]  
• Stormorken, A. T., Bowitz-Lothe, I. M., Noren, T., Kure, E., Aase, S., Wijnen, J., Apold, J., Heimdal, K., Moller, P. (2005). Immunohistochemistry Identifies Carriers of Mismatch Repair Gene Defects Causing Hereditary Nonpolyposis Colorectal Cancer. JCO 23: 4705-4712 [Abstract] [Full Text]  
• Freedman, A. N., Seminara, D., Gail, M. H., Hartge, P., Colditz, G. A., Ballard-Barbash, R., Pfeiffer, R. M. (2005). Cancer Risk Prediction Models: A Workshop on Development, Evaluation, and Application. JNCI J Natl Cancer Inst 97: 715-723 [Abstract] [Full Text]  
• Bian, Y., Caldes, T., Wijnen, J., Franken, P., Vasen, H., Kaklamani, V., Nafa, K., Peterlongo, P., Ellis, N., Baron, J. A., Burn, J., Moeslein, G., Morrison, P. J., Chen, Y., Ahsan, H., Watson, P., Lynch, H. T., de la Chapelle, A., Fodde, R., Pasche, B. (2005). TGFBR1{star}6A May Contribute to Hereditary Colorectal Cancer. JCO 23: 3074-3078 [Abstract] [Full Text]  
• Pinol, V., Castells, A., Andreu, M., Castellvi-Bel, S., Alenda, C., Llor, X., Xicola, R. M., Rodriguez-Moranta, F., Paya, A., Jover, R., Bessa, X., for the Gastrointestinal Oncology Group of the Spa, (2005). Accuracy of Revised Bethesda Guidelines, Microsatellite Instability, and Immunohistochemistry for the Identification of Patients With Hereditary Nonpolyposis Colorectal Cancer. JAMA 293: 1986-1994 [Abstract] [Full Text]  
• Garber, J. E., Offit, K. (2005). Hereditary Cancer Predisposition Syndromes. JCO 23: 276-292 [Abstract] [Full Text]  
• Lipton, L.R., Johnson, V., Cummings, C., Fisher, S., Risby, P., Eftekhar Sadat, A.T., Cranston, T., Izatt, L., Sasieni, P., Hodgson, S.V., Thomas, H.J.W., Tomlinson, I.P.M. (2004). Refining the Amsterdam Criteria and Bethesda Guidelines: Testing Algorithms for the Prediction of Mismatch Repair Mutation Status in the Familial Cancer Clinic. JCO 22: 4934-4943 [Abstract] [Full Text]  
• Sifri, R., Gangadharappa, S., Acheson, L. S. (2004). Identifying and Testing for Hereditary Susceptibility to Common Cancers. CA Cancer J Clin 54: 309-326 [Abstract] [Full Text]  
• Buttin, B. M., Powell, M. A., Mutch, D. G., Rader, J. S., Herzog, T. J., Gibb, R. K., Huettner, P., Edmonston, T. B., Goodfellow, P. J. (2004). Increased Risk for Hereditary Nonpolyposis Colorectal Cancer-Associated Synchronous and Metachronous Malignancies in Patients with Microsatellite Instability-Positive Endometrial Carcinoma Lacking MLH1 Promoter Methylation. Clin. Cancer Res. 10: 481-490 [Abstract] [Full Text]  
• Ferenci, P (2003). How to identify the genetic basis of gastrointestinal and liver diseases?. Gut 52: ii6-9 [Abstract] [Full Text]  
• Chung, D. C., Rustgi, A. K. (2003). The Hereditary Nonpolyposis Colorectal Cancer Syndrome: Genetics and Clinical Implications. ANN INTERN MED 138: 560-570 [Abstract] [Full Text]  
• Mitchell, R. J., Farrington, S. M., Dunlop, M. G., Campbell, H. (2002). Mismatch Repair Genes hMLH1 and hMSH2 and Colorectal Cancer: A HuGE Review. Am J Epidemiol 156: 885-902 [Abstract] [Full Text]  
• Dunlop, M G (2002). Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 51: v21-27 [Full Text]  
• Wahlberg, S. S., Schmeits, J., Thomas, G., Loda, M., Garber, J., Syngal, S., Kolodner, R. D., Fox, E. (2002). Evaluation of Microsatellite Instability and Immunohistochemistry for the Prediction of Germ-Line MSH2 and MLH1 Mutations in Hereditary Nonpolyposis Colon Cancer Families. Cancer Res. 62: 3485-3492 [Abstract] [Full Text]  
• Frayling, I M (2002). Methods of molecular analysis: mutation detection in solid tumours. Mol. Pathol. 55: 73-79 [Abstract] [Full Text]  
• Cravo, M, Afonso, A J, Lage, P, Albuquerque, C, Maia, L, Lacerda, C, Fidalgo, P, Chaves, P, Cruz, C, Nobre-Leitao, C (2002). Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing. Gut 50: 405-412 [Abstract] [Full Text]  
• Bonadona, V., Saltel, P., Desseigne, F., Mignotte, H., Saurin, J.-C., Wang, Q., Sinilnikova, O., Giraud, S., Freyer, G., Plauchu, H., Puisieux, A., Lasset, C. (2002). Cancer Patients Who Experienced Diagnostic Genetic Testing for Cancer Susceptibility: Reactions and Behavior after the Disclosure of a Positive Test Result. Cancer Epidemiol. Biomarkers Prev. 11: 97-104 [Abstract] [Full Text]  
• Raedle, J., Trojan, J., Brieger, A., Weber, N., Schafer, D., Plotz, G., Staib-Sebler, E., Kriener, S., Lorenz, M., Zeuzem, S. (2001). Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer. ANN INTERN MED 135: 566-576 [Abstract] [Full Text]  
• Ramsey, S. D., Clarke, L., Etzioni, R., Higashi, M., Berry, K., Urban, N. (2001). Cost-Effectiveness of Microsatellite Instability Screening as a Method for Detecting Hereditary Nonpolyposis Colorectal Cancer. ANN INTERN MED 135: 577-588 [Abstract] [Full Text]  
• Vasen, H. F.A., Stormorken, A., Menko, F. H., Nagengast, F. M., Kleibeuker, J. H., Griffioen, G., Taal, B. G., Moller, P., Wijnen, J. T. (2001). MSH2 Mutation Carriers Are at Higher Risk of Cancer Than MLH1 Mutation Carriers: A Study of Hereditary Nonpolyposis Colorectal Cancer Families. JCO 19: 4074-4080 [Abstract] [Full Text]  
• Stella, A., Wagner, A., Shito, K., Lipkin, S. M., Watson, P., Guanti, G., Lynch, H. T., Fodde, R., Liu, B. (2001). A Nonsense Mutation in MLH1 Causes Exon Skipping in Three Unrelated HNPCC Families. Cancer Res. 61: 7020-7024 [Abstract] [Full Text]  
• Marra, G., D'Atri, S., Corti, C., Bonmassar, L., Cattaruzza, M. S., Schweizer, P., Heinimann, K., Bartosova, Z., Nystrom-Lahti, M., Jiricny, J. (2001). Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide. Proc. Natl. Acad. Sci. USA 98: 7164-7169 [Abstract] [Full Text]  
• Wagner, A, Hendriks, Y, Meijers-Heijboer, E J, de Leeuw, W J F, Morreau, H, Hofstra, R, Tops, C, Bik, E, Bröcker-Vriends, A H J T, van der Meer, C, Lindhout, D, Vasen, H F A, Breuning, M H, Cornelisse, C J, van Krimpen, C, Niermeijer, M F, Zwinderman, A H, Wijnen, J, Fodde, R (2001). Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. J. Med. Genet. 38: 318-322 [Abstract] [Full Text]  
• Schweizer, P., Moisio, A.-L., Kuismanen, S. A., Truninger, K., Vierumäki, R., Salovaara, R., Arola, J., Butzow, R., Jiricny, J., Peltomäki, P., Nyström-Lahti, M. (2001). Lack of MSH2 and MSH6 Characterizes Endometrial but not Colon Carcinomas in Hereditary Nonpolyposis Colorectal Cancer. Cancer Res. 61: 2813-2815 [Abstract] [Full Text]  
• Lynch, H. T., Lynch, J. (2000). Lynch Syndrome: Genetics, Natural History, Genetic Counseling, and Prevention. JCO 18: 19s-31 [Abstract] [Full Text]  
• Vasen, H. F. A. (2000). Clinical Diagnosis and Management of Hereditary Colorectal Cancer Syndromes. JCO 18: 81s-92 [Full Text]  
• Syngal, S., Fox, E. A, Eng, C., Kolodner, R. D, Garber, J. E (2000). Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J. Med. Genet. 37: 641-645 [Abstract] [Full Text]  
• MONTERA, M., RESTA, N., SIMONE, C., GUANTI, G., MARCHESE, C., CIVITELLI, S., MANCINI, A., POZZI, S., DE SALVO, L., BRUZZONE, D., DONADINI, A., ROMIO, L., MARENI, C. (2000). Mutational germline analysis of hMSH2 and hMLH1 genes in early onset colorectal cancer patients. J. Med. Genet. 37: 7e-7 [Full Text]  
• Syngal, S. (2000). Hereditary Nonpolyposis Colorectal Cancer: A Call for Attention. JCO 18: 2189-2192 [Full Text]  
• Salovaara, R., Loukola, A., Kristo, P., Kaariainen, H., Ahtola, H., Eskelinen, M., Harkonen, N., Julkunen, R., Kangas, E., Ojala, S., Tulikoura, J., Valkamo, E., Jarvinen, H., Mecklin, J.-P., Aaltonen, L. A., de la Chapelle, A. (2000). Population-Based Molecular Detection of Hereditary Nonpolyposis Colorectal Cancer. JCO 18: 2193-2200 [Abstract] [Full Text]  
• LOUKOLA, A., DE LA CHAPELLE, A., AALTONEN, L. A (2000). Correction for vol. 36, p. 819. J. Med. Genet. 37: 479-479 [Full Text]  
• Loukola, A., de la Chapelle, A., Aaltonen, L. A (1999). Strategies for screening for hereditary non-polyposis colorectal cancer. J. Med. Genet. 36: 819-822 [Abstract] [Full Text]  
• Kolodner, R. D., Tytell, J. D., Schmeits, J. L., Kane, M. F., Das Gupta, R., Weger, J., Wahlberg, S., Fox, E. A., Peel, D., Ziogas, A., Garber, J. E., Syngal, S., Anton-Culver, H., Li, F. P. (1999). Germ-line msh6 Mutations in Colorectal Cancer Families. Cancer Res. 59: 5068-5074 [Abstract] [Full Text]  
• Curia, M. C., Palmirotta, R., Aceto, G., Messerini, L., Veri, M. C., Crognale, S., Valanzano, R., Ficari, F., Fracasso, P., Stigliano, V., Tonelli, F., Casale, V., Guadagni, F., Battista, P., Mariani-Costantini, R., Cama, A. (1999). Unbalanced Germ-Line Expression of hMLH1 and hMSH2 Alleles in Hereditary Nonpolyposis Colorectal Cancer. Cancer Res. 59: 3570-3575 [Abstract] [Full Text]  
• Syngal, S., Fox, E. A., Li, C., Dovidio, M., Eng, C., Kolodner, R. D., Garber, J. E. (1999). Interpretation of Genetic Test Results for Hereditary Nonpolyposis Colorectal Cancer: Implications for Clinical Predisposition Testing. JAMA 282: 247-253 [Abstract] [Full Text]  
• O'Leary, T. J. (1999). Molecular Diagnosis of Hereditary Nonpolyposis Colorectal Cancer. JAMA 282: 281-282 [Full Text]  
• Weber, T. K., Chin, H.-M., Rodriguez-Bigas, M., Keitz, B., Gilligan, R., O'Malley, L., Urf, E., Diba, N., Pazik, J., Petrelli, N. J. (1999). Novel hMLH1 and hMSH2 Germline Mutations in African Americans With Colorectal Cancer. JAMA 281: 2316-2320 [Abstract] [Full Text]  
• Guillem, J. G., Aaltonen, L. A., Mecklin, J.-P., de la Chapelle, A. (1998). Molecular Diagnosis of Hereditary Nonpolyposis Colon Cancer. NEJM 339: 924-925 [Full Text]