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a Department of
Medical Genetics, Haartman Institute, University of Helsinki, PO Box
21, FIN-00014 Helsinki, Finland, b Comprehensive Cancer Center, The Ohio State
University, Columbus, Ohio, USA
Correspondence to: Dr Aaltonen.
Revised version received 27 May 1999;
Accepted for publication 17
June 1999
Germline mutations in DNA mismatch repair genes
(MLH1, MSH2,
PMS1, PMS2, and
MSH6) predispose to hereditary non-polyposis colorectal cancer (HNPCC). In the absence of pathognomonic clinical features, diagnosis of HNPCC is often based on family history. Microsatellite instability (MSI) analysis has successfully been used
for screening colorectal cancer patients for HNPCC. The aim of this
study was to evaluate the feasibility of a recently introduced logistical model based on family history data in detecting HNPCC patients with germline mutations. A series of 509 kindreds with a
proband with colorectal cancer was studied. MSI analysis and subsequent germline mutation analysis (MLH1
and MSH2) in MSI positive patients had been
performed previously. Of the 509 patients, 63 (12%) were MSI positive
and 10 (2%) had a germline mutation in MLH1
or MSH2. The power of the logistical model
was tested to determine its value in predicting the probability of a
germline mutation. The model proposed a high probability in three out
of 10 mutation positive cases when data on cancer in first degree relatives were considered (typically three generation pedigrees, consisting, on average, of eight people). Using extended pedigrees and
family cancer data in the 10 mutation positive kindreds (an average of
38 family members available), the model suggested high probabilities in
seven out of 10 mutation positive cases. We conclude that for the model
to predict germline mutation cases, extensive pedigrees and family
history data are required. When screening colorectal cancer patients
for HNPCC, a model using a combination of family information and MSI
has optimal specificity and sensitivity.
This article has been cited by other articles:
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  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]
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 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]
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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]
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R. Salovaara, A. Loukola, P. Kristo, H. Kaariainen, H. Ahtola, M. Eskelinen, N. Harkonen, R. Julkunen, E. Kangas, S. Ojala, et al. Population-Based Molecular Detection of Hereditary Nonpolyposis Colorectal Cancer J. Clin. Oncol., June 11, 2000; 18(11): 2193 - 2200. [Abstract] [Full Text] [PDF]
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A. LOUKOLA, A. DE LA CHAPELLE, and L. A AALTONEN Correction for vol. 36, p. 819 J. Med. Genet., June 1, 2000; 37(6): 479 - 479. [Full Text]
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