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Population-Based Molecular Detection of Hereditary Nonpolyposis Colorectal Cancer

From the Departments of Medical Genetics and Pathology, Haartman Institute, University of Helsinki; the Family Federation of Finland; Second Department of Surgery, Helsinki University Central Hospital; the Folkhälsan Institute of Genetics, Helsinki; Departments of Surgery of the Central Hospitals of Joensuu, Mikkeli, Lappeenranta, Kajaani, Kotka, Savonlinna, and Jyväskylä; Departments of Surgery and Internal Medicine, Kuopio University Hospital, Kuopio, Finland; and the Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH.

Address reprint requests to Albert de la Chapelle, MD, PhD, Division of Human Cancer Genetics, 646 Medical Research Facility, 420 W 12th Ave, Columbus, OH 43210; email delachapelle-1{at}medctr .osu.edu.

PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner.

PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals.

RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population.

CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.

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				M. Scartozzi, F. Bianchi, S. Rosati, E. Galizia, A. Antolini, C. Loretelli, A. Piga, I. Bearzi, R. Cellerino, and E. Porfiri 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., March 1, 2002; 20(5): 1203 - 1208. [Abstract] [Full Text] [PDF]

				A. de la Chapelle Microsatellite Instability Phenotype of Tumors: Genotyping or Immunohistochemistry? The Jury Is Still Out J. Clin. Oncol., February 15, 2002; 20(4): 897 - 899. [Full Text] [PDF]

				P. Laiho, V. Launonen, P. Lahermo, M. Esteller, M. Guo, J. G. Herman, J.-P. Mecklin, H. Jarvinen, P. Sistonen, K.-M. Kim, et al. Low-Level Microsatellite Instability in Most Colorectal Carcinomas Cancer Res., February 1, 2002; 62(4): 1166 - 1170. [Abstract] [Full Text] [PDF]

				J. Raedle, J. Trojan, A. Brieger, N. Weber, D. Schafer, G. Plotz, E. Staib-Sebler, S. Kriener, M. Lorenz, and S. Zeuzem Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer Ann Intern Med, October 16, 2001; 135(8_Part_1): 566 - 576. [Abstract] [Full Text] [PDF]

				S. D. Ramsey, L. Clarke, R. Etzioni, M. Higashi, K. Berry, and N. Urban Cost-Effectiveness of Microsatellite Instability Screening as a Method for Detecting Hereditary Nonpolyposis Colorectal Cancer Ann Intern Med, October 16, 2001; 135(8_Part_1): 577 - 588. [Abstract] [Full Text] [PDF]

				A. Percesepe, F. Borghi, M. Menigatti, L. Losi, M. Foroni, C. Di Gregorio, G. Rossi, M. Pedroni, E. Sala, F. Vaccina, et al. Molecular Screening for Hereditary Nonpolyposis Colorectal Cancer: A Prospective, Population-Based Study J. Clin. Oncol., October 1, 2001; 19(19): 3944 - 3950. [Abstract] [Full Text]

				H. Nakagawa, G. J. Nuovo, E. E. Zervos, E. W. Martin Jr., R. Salovaara, L. A. Aaltonen, and A. de la Chapelle Age-related Hypermethylation of the 5' Region of MLH1 in Normal Colonic Mucosa Is Associated with Microsatellite-unstable Colorectal Cancer Development Cancer Res., October 1, 2001; 61(19): 6991 - 6995. [Abstract] [Full Text] [PDF]

				K. Hemminki, X. Li, and C. Dong Second Primary Cancers after Sporadic and Familial Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., July 1, 2001; 10(7): 793 - 798. [Abstract] [Full Text] [PDF]

				R. B Chadwick, R. E Pyatt, T. H Niemann, S. K Richards, C. K Johnson, M. W Stevens, J. E Meek, H. Hampel, T. W Prior, and A. de la Chapelle Hereditary and somatic DNA mismatch repair gene mutations in sporadic endometrial carcinoma J. Med. Genet., July 1, 2001; 38(7): 461 - 466. [Full Text]

				A. Loukola, K. Eklin, P. Laiho, R. Salovaara, P. Kristo, H. Jarvinen, J.-P. Mecklin, V. Launonen, and L. A. Aaltonen Microsatellite Marker Analysis in Screening for Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Cancer Res., June 1, 2001; 61(11): 4545 - 4549. [Abstract] [Full Text] [PDF]

				W. S. Samowitz, J. A. Holden, K. Curtin, S. L. Edwards, A. R. Walker, H. A. Lin, M. A. Robertson, M. F. Nichols, K. M. Gruenthal, B. J. Lynch, et al. Inverse Relationship between Microsatellite Instability and K-ras and p53 Gene Alterations in Colon Cancer Am. J. Pathol., April 1, 2001; 158(4): 1517 - 1524. [Abstract] [Full Text] [PDF]

				H. Nakagawa, R. B. Chadwick, P. Peltomäki, C. Plass, Y. Nakamura, and A. de la Chapelle Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer PNAS, December 14, 2000; (2000) 11528698. [Abstract] [Full Text]

				A. Loukola, S. Vilkki, J. Singh, V. Launonen, and L. A. Aaltonen Germline and Somatic Mutation Analysis of MLH3 in MSI-Positive Colorectal Cancer Am. J. Pathol., August 1, 2000; 157(2): 347 - 352. [Abstract] [Full Text] [PDF]

				S. Syngal Hereditary Nonpolyposis Colorectal Cancer: A Call for Attention J. Clin. Oncol., June 11, 2000; 18(11): 2189 - 2192. [Full Text] [PDF]

				H. Nakagawa, R. B. Chadwick, P. Peltomaki, C. Plass, Y. Nakamura, and A. de la Chapelle From the Cover: Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer PNAS, January 16, 2001; 98(2): 591 - 596. [Abstract] [Full Text] [PDF]