This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vasen, H. F.A. Articles by Wijnen, J. T. Search for Related Content PubMed PubMed Citation Articles by Vasen, H. F.A. Articles by Wijnen, J. T. Social Bookmarking                            What's this?

MSH2 Mutation Carriers Are at Higher Risk of Cancer Than MLH1 Mutation Carriers: A Study of Hereditary Nonpolyposis Colorectal Cancer Families

From the Netherlands Foundation for the Detection of Hereditary Tumors; Departments of Gastroenterology and Clinical and Human Genetics, Leiden University Medical Centre, Leiden; Department of Gastroenterology, University Hospital Radboud, Nijmegen; and Department of Gastroenterology, University Hospital Groningen, Groningen, the Netherlands; Department of Clinical Genetics, Radiumhospital, Oslo, Norway; Department of Clinical and Human Genetics, University Hospital Vrije Universiteit; and Department of Medical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, the Netherlands.

Address reprint requests to H.F.A.Vasen, MD, PhD, Netherlands Foundation for the Detection of Hereditary Tumours, Leiden University Medical Centre, Poortgebouw Zuid, 2333 AA Leiden, the Netherlands; email: nfdht{at}xs4all.nl

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations.

PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives.

RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant.

CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				F. Kastrinos, B. Mukherjee, N. Tayob, F. Wang, J. Sparr, V. M. Raymond, P. Bandipalliam, E. M. Stoffel, S. B. Gruber, and S. Syngal Risk of Pancreatic Cancer in Families With Lynch Syndrome JAMA, October 28, 2009; 302(16): 1790 - 1795. [Abstract] [Full Text] [PDF]

				E. M. Grindedal, P. Moller, R. Eeles, A. T. Stormorken, I. M. Bowitz-Lothe, S. M. Landro, N. Clark, R. Kvale, S. Shanley, and L. Maehle Germ-Line Mutations in Mismatch Repair Genes Associated with Prostate Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2009; 18(9): 2460 - 2467. [Abstract] [Full Text] [PDF]

				L. Maehle, J. Apold, T. Paulsen, B. Hagen, K. Lovslett, B. Fiane, M. Van Ghelue, N. Clark, and P. Moller High Risk for Ovarian Cancer in a Prospective Series Is Restricted to BRCA1/2 Mutation Carriers Clin. Cancer Res., November 15, 2008; 14(22): 7569 - 7573. [Abstract] [Full Text] [PDF]

				F. Kastrinos, E. M. Stoffel, J. Balmana, E. W. Steyerberg, R. Mercado, and S. Syngal Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 2044 - 2051. [Abstract] [Full Text] [PDF]

				A.H.S. Gylling, T.T. Nieminen, W.M. Abdel-Rahman, K. Nuorva, M. Juhola, E.I. Joensuu, H.J. Jarvinen, J.-P. Mecklin, M. Aarnio, and P.T. Peltomaki Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors Carcinogenesis, July 1, 2008; 29(7): 1351 - 1359. [Abstract] [Full Text] [PDF]

				M. D. Walsh, M. C. Cummings, D. D. Buchanan, W. M. Dambacher, S. Arnold, D. McKeone, R. Byrnes, M. A. Barker, B. A. Leggett, M. Gattas, et al. Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients Clin. Cancer Res., March 15, 2008; 14(6): 1692 - 1700. [Abstract] [Full Text] [PDF]

				L. A Devlin and P. J Morrison Inherited gynaecological cancer syndromes Obstet Gynaecol (Lond), January 1, 2008; 10(1): 9 - 15. [Abstract] [Full Text] [PDF]

				K. H. Lu, J. O. Schorge, K. J. Rodabaugh, M. S. Daniels, C. C. Sun, P. T. Soliman, K. G. White, R. Luthra, D. M. Gershenson, and R. R. Broaddus Prospective Determination of Prevalence of Lynch Syndrome in Young Women With Endometrial Cancer J. Clin. Oncol., November 20, 2007; 25(33): 5158 - 5164. [Abstract] [Full Text] [PDF]

				G L ten Kate, J H Kleibeuker, F M Nagengast, M Craanen, A Cats, F H Menko, and H F A Vasen Is surveillance of the small bowel indicated for Lynch syndrome families? Gut, September 1, 2007; 56(9): 1198 - 1201. [Abstract] [Full Text] [PDF]

				H. T. Lynch, C. R. Boland, M. A. Rodriguez-Bigas, C. Amos, J. F. Lynch, and P. M. Lynch Who Should Be Sent for Genetic Testing in Hereditary Colorectal Cancer Syndromes? J. Clin. Oncol., August 10, 2007; 25(23): 3534 - 3542. [Abstract] [Full Text] [PDF]

				A Gylling, W M Abdel-Rahman, M Juhola, K Nuorva, E Hautala, H J Jarvinen, J-P Mecklin, M Aarnio, and P Peltomaki Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study Gut, July 1, 2007; 56(7): 926 - 933. [Abstract] [Full Text] [PDF]

				B. Halvarsson, W. Muller, M. Planck, A. C. Benoni, P. Mangell, J. Ottosson, M. Hallen, A. Isinger, and M. Nilbert Phenotypic heterogeneity in hereditary non-polyposis colorectal cancer: identical germline mutations associated with variable tumour morphology and immunohistochemical expression J. Clin. Pathol., July 1, 2007; 60(7): 781 - 786. [Abstract] [Full Text] [PDF]

				H F A Vasen, G Moslein, A Alonso, I Bernstein, L Bertario, I Blanco, J Burn, G Capella, C Engel, I Frayling, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer) J. Med. Genet., June 1, 2007; 44(6): 353 - 362. [Abstract] [Full Text] [PDF]

				N. M. Lindor, G. M. Petersen, D. W. Hadley, A. Y. Kinney, S. Miesfeldt, K. H. Lu, P. Lynch, W. Burke, and N. Press Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA, September 27, 2006; 296(12): 1507 - 1517. [Abstract] [Full Text] [PDF]

				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]

				J.-G. Park, D.-W. Kim, C. W. Hong, B.-H. Nam, Y.-K. Shin, S.-H. Hong, I.-J. Kim, S.-B. Lim, M. Aronson, M. L. Bisgaard, et al. Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: international society for gastrointestinal hereditary tumours collaborative study. Clin. Cancer Res., June 1, 2006; 12(11): 3389 - 3393. [Abstract] [Full Text] [PDF]

				K. M. Schmeler, H. T. Lynch, L.-m. Chen, M. F. Munsell, P. T. Soliman, M. B. Clark, M. S. Daniels, K. G. White, S. G. Boyd-Rogers, P. G. Conrad, et al. Prophylactic Surgery to Reduce the Risk of Gynecologic Cancers in the Lynch Syndrome N. Engl. J. Med., January 19, 2006; 354(3): 261 - 269. [Abstract] [Full Text] [PDF]

				S Kruger, A Bier, C Engel, E Mangold, C Pagenstecher, M von Knebel Doeberitz, E Holinski-Feder, G Moeslein, K Schulmann, J Plaschke, et al. The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC) J. Med. Genet., October 1, 2005; 42(10): 769 - 773. [Abstract] [Full Text] [PDF]

				K. Sotamaa, S. Liyanarachchi, J.-P. Mecklin, H. Jarvinen, L. A. Aaltonen, P. Peltomaki, and A. de la Chapelle p53 Codon 72 and MDM2 SNP309 Polymorphisms and Age of Colorectal Cancer Onset in Lynch Syndrome Clin. Cancer Res., October 1, 2005; 11(19): 6840 - 6844. [Abstract] [Full Text] [PDF]

				S. Chen, P. Watson, and G. Parmigiani Accuracy of MSI testing in predicting germline mutations of MSH2 and MLH1: a case study in Bayesian meta-analysis of diagnostic tests without a gold standard Biostat., July 1, 2005; 6(3): 450 - 464. [Abstract] [Full Text] [PDF]

				F Quehenberger, H F A Vasen, and H C van Houwelingen Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment J. Med. Genet., June 1, 2005; 42(6): 491 - 496. [Abstract] [Full Text] [PDF]

				W Kievit, J H F M de Bruin, E M M Adang, J L Severens, J H Kleibeuker, R H Sijmons, T J Ruers, F M Nagengast, H F A Vasen, J H J M van Krieken, et al. Cost effectiveness of a new strategy to identify HNPCC patients Gut, January 1, 2005; 54(1): 97 - 102. [Abstract] [Full Text] [PDF]

				P. Watson, R. Ashwathnarayan, H. T. Lynch, and H. K. Roy Tobacco Use and Increased Colorectal Cancer Risk in Patients With Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Arch Intern Med, December 13, 2004; 164(22): 2429 - 2431. [Abstract] [Full Text] [PDF]

				J. Plaschke, C. Engel, S. Kruger, E. Holinski-Feder, C. Pagenstecher, E. Mangold, G. Moeslein, K. Schulmann, J. Gebert, M. von Knebel Doeberitz, et al. Lower Incidence of Colorectal Cancer and Later Age of Disease Onset in 27 Families With Pathogenic MSH6 Germline Mutations Compared With Families With MLH1 or MSH2 Mutations: The German Hereditary Nonpolyposis Colorectal Cancer Consortium J. Clin. Oncol., November 15, 2004; 22(22): 4486 - 4494. [Abstract] [Full Text] [PDF]

				E Mangold, C Pagenstecher, M Leister, M Mathiak, A Rutten, W Friedl, P Propping, T Ruzicka, and R Kruse A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome J. Med. Genet., July 1, 2004; 41(7): 567 - 572. [Full Text] [PDF]

				W H de Vos tot Nederveen Cappel, E Buskens, P van Duijvendijk, A Cats, F H Menko, G Griffioen, J F Slors, F M Nagengast, J H Kleibeuker, and H F A Vasen Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect Gut, December 1, 2003; 52(12): 1752 - 1755. [Abstract] [Full Text] [PDF]

				M. J.W. Berends, Y. Wu, R. H. Sijmons, T. van der Sluis, W. B. Ek, M. J.L. Ligtenberg, N. J.W. Arts, K. A. ten Hoor, J. H. Kleibeuker, E. G.E. de Vries, et al. Toward New Strategies to Select Young Endometrial Cancer Patients for Mismatch Repair Gene Mutation Analysis J. Clin. Oncol., December 1, 2003; 21(23): 4364 - 4370. [Abstract] [Full Text] [PDF]

				Y Parc, C Boisson, G Thomas, and S Olschwang Cancer risk in 348 French MSH2 or MLH1 gene carriers J. Med. Genet., March 1, 2003; 40(3): 208 - 213. [Full Text] [PDF]

				R. J. Mitchell, S. M. Farrington, M. G. Dunlop, and H. Campbell Mismatch Repair Genes hMLH1 and hMSH2 and Colorectal Cancer: A HuGE Review Am. J. Epidemiol., November 15, 2002; 156(10): 885 - 902. [Abstract] [Full Text] [PDF]