Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients.
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.
Russo
Antonio
A
Epidemiology Unit, San Carlo Hospital, Milan, Italy.
Sala
Paola
P
Alberici
Paola
P
Gazzoli
Isabella
I
Radice
Paolo
P
Montefusco
Claudia
C
Torrini
Margherita
M
Mareni
Cristina
C
Fornasarig
Mara
M
Santarosa
Manuela
M
Viel
Alessandra
A
Benatti
Piero
P
Pedroni
Monica
M
Pedroni
Maurizio
M
de Leon
Maurizio Ponz
MP
Lucci-Cordisco
Emanuela
E
Genuardi
Maurizio
M
Messerini
Luca
L
Stigliano
Vittoria
V
Cama
Alessandro
A
Curia
Maria Cristina
MC
de Lellis
Laura
L
Signoroni
Stefano
S
Pierotti
Marco A
MA
Bertario
Lucio
L
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
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