Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients

Antonio Russo, Paola Sala, Paola Alberici, Isabella Gazzoli, Paolo Radice, Claudia Montefusco, Margherita Torrini, Cristina Mareni, Mara Fornasarig, Manuela Santarosa, Alessandra Viel, Piero Benatti, Maurizio Pedroni, Maurizio Ponz De Leon, Emanuela Lucci-Cordisco, Maurizio Genuardi, Luca Messerini, Vittoria Stigliano, Alessandro Cama, Maria Cristina CuriaLaura De Lellis, Stefano Signoroni, Marco A. Pierotti, Lucio Bertario

Research output: Contribution to journalArticlepeer-review


Aims and background. 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.

Original languageEnglish
Pages (from-to)731-738
Number of pages8
Issue number6
Publication statusPublished - Nov 2009


  • Hereditary non-polyposis colorectal cancer
  • MLH1
  • MSH2
  • Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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