title: Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway.
abstract: OBJECTIVE
  Hereditary nonpolyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer. Whereas it has been known that mismatch repair gene mutations are the underlying cause of HNPCC, an undetermined number of patients do not have these alterations. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features.
  
  
  METHODS
  This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations.
  
  
  RESULTS
  Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers.
  
  
  CONCLUSIONS
  We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.
authors.affiliation: Gastroenterology Department, Germans Trias i Pujol Hospital, Universitat Autonòma de Barcelona, Spain. xllor@comb.es
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.forename: Elisenda
authors.initials: E
authors.lastname: Pons
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Xicola
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Cristina
authors.initials: C
authors.lastname: Alenda
authors.forename: Virgínia
authors.initials: V
authors.lastname: Piñol
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
authors.forename: Artemio
authors.initials: A
authors.lastname: Payá
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.forename: Xavier
authors.initials: X
authors.lastname: Bessa
authors.forename: Anna
authors.initials: A
authors.lastname: Girós
authors.forename: Anna
authors.initials: A
authors.lastname: Roca
authors.forename: Miquel A
authors.initials: MA
authors.lastname: Gassull
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D011446:Prospective Studies; D013030:Spain
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein