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 MLITH-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% Cl, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% Cl, 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% Cl, 0.51-0.981 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.
Russo, A., Sala, P., Alberici, P., Gazzoli, I., Radice, P., Montefusco, C., Torrini, M., Mareni, C., Fornasarig, M., Santarosa, M., Viel, A., Benatti, P., Pedroni, M., De Leon, M., Lucci Cordisco, E., Genuardi, M., Messerini, L., Stigliano, V., Cama, A., Curia, M., De Lellis, L., Signoroni, S., Pierotti, M., Bertario, L., Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients, <<TUMORI>>, 2009; 95 (6): 731-738. [doi:10.1177/030089160909500616] [http://hdl.handle.net/10807/57720]
Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients
Lucci Cordisco, E;Genuardi, Maurizio;
2009
Abstract
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 MLITH-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% Cl, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% Cl, 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% Cl, 0.51-0.981 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.
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