title: Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients.
abstract: OBJECTIVE
  Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients.
  
  
  METHODS
  A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family.
  
  
  RESULTS
  Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006).
  
  
  CONCLUSIONS
  Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.
authors.affiliation: Epidemiology Unit, San Carlo Hospital, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Paola
authors.initials: P
authors.lastname: Sala
authors.forename: Paola
authors.initials: P
authors.lastname: Alberici
authors.forename: Isabella
authors.initials: I
authors.lastname: Gazzoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Claudia
authors.initials: C
authors.lastname: Montefusco
authors.forename: Margherita
authors.initials: M
authors.lastname: Torrini
authors.forename: Cristina
authors.initials: C
authors.lastname: Mareni
authors.forename: Mara
authors.initials: M
authors.lastname: Fornasarig
authors.forename: Manuela
authors.initials: M
authors.lastname: Santarosa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.forename: Piero
authors.initials: P
authors.lastname: Benatti
authors.forename: Monica
authors.initials: M
authors.lastname: Pedroni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pedroni
authors.forename: Maurizio Ponz
authors.initials: MP
authors.lastname: de Leon
authors.forename: Emanuela
authors.initials: E
authors.lastname: Lucci-Cordisco
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Luca
authors.initials: L
authors.lastname: Messerini
authors.forename: Vittoria
authors.initials: V
authors.lastname: Stigliano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cama
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Curia
authors.forename: Laura
authors.initials: L
authors.lastname: de Lellis
authors.forename: Stefano
authors.initials: S
authors.lastname: Signoroni
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Lucio
authors.initials: L
authors.lastname: Bertario
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology*; D053843:DNA Mismatch Repair; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein