title: Population-based molecular detection of hereditary nonpolyposis colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Medical Genetics and Pathology, Haartman Institute, University of Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Salovaara
authors.forename: A
authors.initials: A
authors.lastname: Loukola
authors.forename: P
authors.initials: P
authors.lastname: Kristo
authors.forename: H
authors.initials: H
authors.lastname: Kääriäinen
authors.forename: H
authors.initials: H
authors.lastname: Ahtola
authors.forename: M
authors.initials: M
authors.lastname: Eskelinen
authors.forename: N
authors.initials: N
authors.lastname: Härkönen
authors.forename: R
authors.initials: R
authors.lastname: Julkunen
authors.forename: E
authors.initials: E
authors.lastname: Kangas
authors.forename: S
authors.initials: S
authors.lastname: Ojala
authors.forename: J
authors.initials: J
authors.lastname: Tulikoura
authors.forename: E
authors.initials: E
authors.lastname: Valkamo
authors.forename: H
authors.initials: H
authors.lastname: Järvinen
authors.forename: J P
authors.initials: JP
authors.lastname: Mecklin
authors.forename: L A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: A
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000032:analysis*; D005260:Female; D005387:Finland / Q000453:epidemiology; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D012042:Registries
chemical_list: D004273:DNA, Neoplasm; D005819:Genetic Markers