title: Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma.
abstract: BACKGROUND
  The Amsterdam criteria are used worldwide for the clinical diagnosis of hereditary nonpolyposis colorectal carcinoma (HNPCC). In Japan, clinical criteria (JCC) have been proposed to identify as many HNPCC cases as possible, but the suitability of the JCC remains uncertain. In this article, the authors evaluate retrospectively whether the JCC are adequate to diagnose HNPCC compared with the Bethesda guidelines (BG) and also investigated useful screening methods for HNPCC.
  
  
  METHODS
  The authors studied 452 colorectal carcinoma cases, of which 69 cases fulfilled the JCC (A, 12; B, 57) and 106 fulfilled the BG. Microsatellite instability (MSI) was examined for 452 cases. TGF beta RII, immunohistochemical staining, and germline mutations of hMLH1 and hMSH2 were analyzed in high-frequency MSI cases.
  
  
  RESULTS
  High-frequency MSI was found in 21.7% (98 of 452). Germline mutations were detected in eight cases (hMLH1, three, hMSH2; five). Six cases fulfilled the JCC (A, four; B, two), and six fulfilled the BG. The germline mutation rate was significantly higher in the JCCA than in non-JCCA cases (33.3% vs. 0.91%; P < 0.001) and in cases with an age at onset younger than 50 years than older than 50 years (9.3% vs. 0.27%, P < 0.001). All germline mutation carriers had the TGF beta RII mutation. Immunohistochemically, a decreased nuclear staining was found in 57.3% (47 of 82) for hMLH1 and in 18.3% (15 of 82) for hMSH2. The frequency of predicted germline mutations was higher in cases with decreased hMSH2 than hMLH1 (33.3% vs. 6.4%; P = 0.016).
  
  
  CONCLUSIONS
  The JCCA are suitable for selecting cases to analyze for gene mutations, but the JCCB are not useful for the clinical setting. The authors suggest that an age at onset younger than 50 years is also important for screening. Analyzing TGF beta RII mutations and immunohistochemical staining of hMLH1 or hMSH2 for cases with MSI phenotype are useful for selecting cases who should be tested for germline mutations.
authors.affiliation: Department of Surgery, Jichi Medical School, Kawachi-gun, Tochigi, Japan. furukawa@jichi.ac.jp
authors.forename: Taiji
authors.initials: T
authors.lastname: Furukawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Konishi
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Shitoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kojima
authors.forename: Hideo
authors.initials: H
authors.lastname: Nagai
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008403:Mass Screening; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein