This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weber, T. K. Articles by Yandell, D. Search for Related Content PubMed PubMed Citation Articles by Weber, T. K. Articles by Yandell, D.

Genomic DNA-based hMSH2 and hMLH1 Mutation Screening in 32 Eastern United States Hereditary Nonpolyposis Colorectal Cancer Pedigrees¹

Departments of Surgery [T. K. W., N. J. P., M. R-B., B. K., J. P., C. F., L. O., M. O., M. A.] and Cell and Molecular Biology [G. A., D. S.], Roswell Park Cancer Institute, Buffalo, New York 14263, and Vermont Cancer Center and Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05410 [W. C., D. Y.]

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome characterized by early age of onset colorectal cancer (mean 45 years) as well as endometrial, urinary tract, and upper gastrointestinal adenocarcinomas. The HNPCC phenotype has been shown to segregate with germline mutations in the human homologues of the DNA mismatch repair genes MSH2, MLH1, PMS1, and PMS2. However, the majority of published DNA mismatch repair gene mutation surveys associated with HNPCC kindreds report multiple levels of prese-lection, including 2p and 3p chromosomal linkage analysis and the evaluation of microsatellite instability of proband colorectal cancers prior to mutation analysis. For this reason, the concise contribution of each of the known DNA mismatch repair genes to the HNPCC phenotype remains unknown. We report the results of a genomic DNA-based analysis of hMSH2 and hMLH1 germline mutations in 32 unrelated Eastern United States HNPCC kindreds. These families were selected for study on the basis of phenotype only. We identified three hMSH2 and six hMLH1 mutations in eight families, for a positive mutation rate of 25%. Two mutations were identified in one of the families. Four of the mutations detected have not been reported in the literature previously. One of the mutation-positive families is African American; the others were of European-American ancestry. These results provide a clarification of the contribution of hMSH2 and hMLH1 to the HNPCC phenotype and suggest that in the majority of Eastern United States HNPCC kindreds selected by phenotype alone, the molecular genetic basis for the disease remains unknown.

¹ This work was supported by a grant from the Research Foundation of the American Society of Colorectal Surgeons and National Cancer Institute Cancer Center Support Grant P30 CA-16056. T. K. W. is an American Cancer Society Career Development Awardee.

² To whom requests for reprints should be addressed, at Department of Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets. Buffalo, NY 14263.

Received 4/23/97. Accepted 7/ 7/97.

This article has been cited by other articles:

				T. Goecke, K. Schulmann, C. Engel, E. Holinski-Feder, C. Pagenstecher, H. K. Schackert, M. Kloor, E. Kunstmann, H. Vogelsang, G. Keller, et al. Genotype-Phenotype Comparison of German MLH1 and MSH2 Mutation Carriers Clinically Affected With Lynch Syndrome: A Report by the German HNPCC Consortium J. Clin. Oncol., September 10, 2006; 24(26): 4285 - 4292. [Abstract] [Full Text] [PDF]

				M. O. Woods, A. J. Hyde, F. K. Curtis, S. Stuckless, J. S. Green, A. F. Pollett, J. D. Robb, R. C. Green, M. E. Croitoru, A. Careen, et al. High Frequency of Hereditary Colorectal Cancer in Newfoundland Likely Involves Novel Susceptibility Genes Clin. Cancer Res., October 1, 2005; 11(19): 6853 - 6861. [Abstract] [Full Text] [PDF]

				S. Oda, Y. Maehara, Y. Ikeda, E. Oki, A. Egashira, Y. Okamura, I. Takahashi, Y. Kakeji, Y. Sumiyoshi, K. Miyashita, et al. Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability Nucleic Acids Res., March 18, 2005; 33(5): 1628 - 1636. [Abstract] [Full Text] [PDF]

				J. Listgarten, S. Damaraju, B. Poulin, L. Cook, J. Dufour, A. Driga, J. Mackey, D. Wishart, R. Greiner, and B. Zanke Predictive Models for Breast Cancer Susceptibility from Multiple Single Nucleotide Polymorphisms Clin. Cancer Res., April 15, 2004; 10(8): 2725 - 2737. [Abstract] [Full Text] [PDF]

				E. Renkonen, Y. Zhang, H. Lohi, R. Salovaara, W. M. Abdel-Rahman, M. Nilbert, K. Aittomaki, H. J. Jarvinen, J.-P. Mecklin, A. Lindblom, et al. Altered Expression of MLH1, MSH2, and MSH6 in Predisposition to Hereditary Nonpolyposis Colorectal Cancer J. Clin. Oncol., October 1, 2003; 21(19): 3629 - 3637. [Abstract] [Full Text] [PDF]

				M Palicio, J Balmana, S Gonzalez, I Blanco, E Marcuello, M A Peinado, G Julia, J R Germa, J J Lopez Lopez, J Brunet, et al. Mismatch repair gene analysis in Catalonian families with colorectal cancer J. Med. Genet., June 1, 2002; 39(6): e29 - 29. [Full Text] [PDF]

				H. Yamamoto, F. Itoh, H. Nakamura, H. Fukushima, S. Sasaki, M. Perucho, and K. Imai Genetic and Clinical Features of Human Pancreatic Ductal Adenocarcinomas with Widespread Microsatellite Instability Cancer Res., April 1, 2001; 61(7): 3139 - 3144. [Abstract] [Full Text]

				M. C. Curia, R. Palmirotta, G. Aceto, L. Messerini, M. C. Veri, S. Crognale, R. Valanzano, F. Ficari, P. Fracasso, V. Stigliano, et al. Unbalanced Germ-Line Expression of hMLH1 and hMSH2 Alleles in Hereditary Nonpolyposis Colorectal Cancer Cancer Res., August 1, 1999; 59(15): 3570 - 3575. [Abstract] [Full Text] [PDF]

				S. Syngal, E. A. Fox, C. Li, M. Dovidio, C. Eng, R. D. Kolodner, and J. E. Garber Interpretation of Genetic Test Results for Hereditary Nonpolyposis Colorectal Cancer: Implications for Clinical Predisposition Testing JAMA, July 21, 1999; 282(3): 247 - 253. [Abstract] [Full Text] [PDF]

				M P. de Leon, M Pedroni, P Benatti, A Percesepe, C Di Gregorio, M Foroni, G Rossi, M Genuardi, G Neri, F Leonardi, et al. Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis Gut, July 1, 1999; 45(1): 32 - 38. [Abstract] [Full Text] [PDF]

				T. K. Weber, H.-M. Chin, M. Rodriguez-Bigas, B. Keitz, R. Gilligan, L. O'Malley, E. Urf, N. Diba, J. Pazik, and N. J. Petrelli Novel hMLH1 and hMSH2 Germline Mutations in African Americans With Colorectal Cancer JAMA, June 23, 1999; 281(24): 2316 - 2320. [Abstract] [Full Text] [PDF]

				H. T. Lynch, M. J. Casey, T. G. Shaw, and J. F. Lynch Hereditary Factors in Gynecologic Cancer Oncologist, October 1, 1998; 3(5): 319 - 338. [Abstract] [Full Text]

				J. T. Wijnen, H. F.A. Vasen, P. M. Khan, A. H. Zwinderman, H. van der Klift, A. Mulder, C. Tops, P. Moller, R. Fodde, F. Menko, et al. Clinical Findings with Implications for Genetic Testing in Families with Clustering of Colorectal Cancer N. Engl. J. Med., August 20, 1998; 339(8): 511 - 518. [Abstract] [Full Text] [PDF]

				M. De las Alas, R. A. M. de bruin, L. T. Eyck, G. Los, and S. B. Howell Prediction-based threading of the hMSH2 DNA mismatch repair protein FASEB J, June 1, 1998; 12(9): 653 - 663. [Abstract] [Full Text]