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Arch Hellen Med, 23(5), September-October 2006, 473-482


Tissue microarrays in immunohistochemical expression and molecular detection of DNA MMR system instability in colorectal cancer

1Department of Pathology, Laboratory of Image Analysis, 417 VA Hospital,
2Department of Surgery, 417 VA Hospital,
3Department of Clinical Cytology,
417 VA Hospital, 4Experimental Surgery Unit, Medical School, University of Athens, Athens, Greece

OBJECTIVE To evaluate immunohistochemical expression DNA MMR (mismatch repair system) proteins (MLH1, MSH2 and MSH6-GTBP) in sporadic colon adenocarcinomas, correlating the results with chromosomal instability of chromosome 2, 3, 9, 16 and 17. Microsatellite instability (MSI) in colorectal tumors can be detected in up to 15% of incident colorectal cancers. MSI in sporadic colorectal cancers is primarily due to epigenetic silencing of MLH1, while MSI is almost universal in tumors from HNPCC family members due to germline MMR gene mutation with loss or mutational inactivation of the second copy as a somatic event. There is evidence that tumor MSI is associated with a better outcome than the rest of large bowel malignancy.

METHOD Using tissue microarrays technology one paraffin block was created in which were embedded 60 histologically confirmed colon adenocarcinoma samples with a core diameter of 1 mm. Immunohistochemistry and chromogenic in situ hybridization were performed using an automated staining system. A computerized image analysis method was applied by the use of a semi-automated system. Statistical analysis was performed using the SPSS program.

RESULTS Loss or low levels of expression were observed in 8/60 (13%) cases. A high predominance of this event was observed in the expression of MLH1 (7/8, 85%). Aneuploidy of chromosome 2, 9, 16 and 17 was detected predominantly in the group of immunohistochemically stable cancers. In addition, 75% of cases which demonstrated combined loss of expression in at least 2 markers were characterized by lymphocytic infiltration.

CONCULSIONS Chromosomal instability is a common genetic event in colorectal cancers. A subset characterized by microsatellite instability and loss of expression in DNA MMR genes correlates with better prognosis (longer survival, response to chemotherapy).

Key words: Colorectal cancer, DNA MMR, Tissue microarrays.

© Archives of Hellenic Medicine