title: Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer.
abstract: BACKGROUND
  Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations.
  
  
  OBJECTIVE
  To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients.
  
  
  METHODS
  In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours.
  
  
  RESULTS
  25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years.
  
  
  CONCLUSIONS
  Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.
authors.affiliation: Department of Gastroenterology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: R C
authors.initials: RC
authors.lastname: Niessen
authors.forename: M J W
authors.initials: MJ
authors.lastname: Berends
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: R H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: H
authors.initials: H
authors.lastname: Hollema
authors.forename: M J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: H E K
authors.initials: HE
authors.lastname: de Walle
authors.forename: E G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: A
authors.initials: A
authors.lastname: Karrenbeld
authors.forename: C H C M
authors.initials: CH
authors.lastname: Buys
authors.forename: A G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: R M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: J H
authors.initials: JH
authors.lastname: Kleibeuker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011237:Predictive Value of Tests
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein