Is reduced expression of mismatch repair genes MLH1 and MSH2 in patients with sporadic colorectal cancer related to their prognosis?
The majority of mutations in hereditary nonpolyposis colon carcinoma (HNPCC) patients affect the mismatch-repair genes (MMRG) MLHI and MSH2. In addition, mutations of these genes were found in about 15% of sporadic colorectal carcinomas which appear to be related to microsatellite instability (MSI). However, mutations in MMRG were not found in all MSI-positive carcinomas, but MMRG mutations may be relevant for the assessment of tumor characteristics and patients' prognosis. Therefore, we investigated the relationship between expression of MMRG, tumor biology and patients' survival. In 127 patients with sporadic colorectal carcinomas and a minimum of 5 years follow-up after curative surgery immunohistochemical detection of MLHI and MSH2 was analyzed semiquantitatively. Lost expression of MLHI has been found in tumor specimens from 10 patients, whereas MSH2 expression was missing in 5 patients. This reduced expression did not correlate with tumor stage, lymph node involvement, grading or tumor invasion into blood vessels. However, a significant correlation was found for lymphovascular invasion (P = 0.02) and localization within the colorectum (P = 0.003) in MLH1-negative carcinomas. In addition, although there was a clear tendency for longer overall survival (72 vs. 63 months) for patients with MLH1-negative carcinomas, significant differences for overall and recurrence-free survival were not seen. In conclusion of our results and a critical review of literature, the prognostic importance of the MMR genes in sporadic colorectal carcinomas remains controversial.
Kruschewski
Martin
M
Department of Surgery, University Hospital Benjamin Franklin, Free University of Berlin, Germany. kruschewski@ukbf.fu-berlin.de
Noske
Aurelia
A
Haier
Jörg
J
Runkel
Norbert
N
Anagnostopoulos
Yanis
Y
Buhr
Heinz Johannes
HJ
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D016019:Survival Analysis
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein